The Role of the Mammalian Target of Rapamycin (mTOR) in Pulmonary Fibrosis

Jessica Lawrence, Richard Nho, Jessica Lawrence, Richard Nho

Abstract

The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-dependent pathway is one of the most integral pathways linked to cell metabolism, proliferation, differentiation, and survival. This pathway is dysregulated in a variety of diseases, including neoplasia, immune-mediated diseases, and fibroproliferative diseases such as pulmonary fibrosis. The mTOR kinase is frequently referred to as the master regulator of this pathway. Alterations in mTOR signaling are closely associated with dysregulation of autophagy, inflammation, and cell growth and survival, leading to the development of lung fibrosis. Inhibitors of mTOR have been widely studied in cancer therapy, as they may sensitize cancer cells to radiation therapy. Studies also suggest that mTOR inhibitors are promising modulators of fibroproliferative diseases such as idiopathic pulmonary fibrosis (IPF) and radiation-induced pulmonary fibrosis (RIPF). Therefore, mTOR represents an attractive and unique therapeutic target in pulmonary fibrosis. In this review, we discuss the pathological role of mTOR kinase in pulmonary fibrosis and examine how mTOR inhibitors may mitigate fibrotic progression.

Keywords: fibrosis; idiopathic pulmonary fibrosis (IPF); mammalian target of rapamycin (mTOR); phosphoinositide 3-kinase (PI3K); protein kinase B (AKT); radiation-induced pulmonary fibrosis (RIPF).

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Proposed model for IPF. Chronic lung injury promotes lung epithelial cell death while (myo)fibroblasts become activated as a result of fibrosis inducing growth factors and cytokines. The failure of re-epithelization and hyper-proliferation of (myo)fibroblasts relentlessly produce collagen rich extracellular matrix, which promotes the fibrotic process, leading to the progression of lung fibrosis.
Figure 2
Figure 2
Schematic figure describing the development of radiation-induced chronic lung fibrosis. Radiation causes damage to pneumocytes and induces secondary reactive oxygen species that contribute to a pro-inflammatory environment. Acutely injured lung triggers healing mechanisms that activate (myo)fibroblasts. Excessive accumulation of collagen, which normally inhibits further fibroblast growth, selects for pro-fibrotic, viable lung fibroblasts. Fibroblast activation and selection combined with the inflammatory cytokine cascade, epithelial to mesenchymal transition (EMT), and loss of parenchymal cells leads to ongoing lung fibrosis. The bidirectional arrow indicates that cell death creates inflammatory cytokine production which further increases cell death.
Figure 3
Figure 3
mTORC1 and mTORC2 complexes and environmental signals to regulate the PI3K/AKT/mTOR pathway to influence growth, proliferation and survival. T indicates the inhibition of the target molecule.
Figure 4
Figure 4
mTOR regulates cell growth, proliferation, and survival. The arrows indicates positive regulation while the symbol T indicates the inhibition of the target molecule(s).
Figure 5
Figure 5
Proposed mechanism by which mTOR may contribute to radiosensitivity and DNA damage repair and thereby potential means in which inhibition of mTORC1 or mTORC2 may alter cell cycle arrest, DNA repair and cell survival following radiation. Pathologic pro-fibrotic lung fibroblasts may depend on both mTORC1 and mTORC2 for efficient cell cycle arrest and repair of DNA damage following radiation damage. In non-radiation induced lung damage, DNA damage may result from various chemical or other microinjuries that create a similar population of fibroblasts that depend on mTOR complexes for survival and proliferation. The bidirectional arrow indicates that AKT activates mTORC2 while mTORC2 can also positively impact PI3K/AKT signaling. T indicates the inhibition of the target molecule. The purple “bolt” indicates ionizing radiation.
Figure 6
Figure 6
Schematic describing potential interactions of mTOR and TGF-β, a major driver of lung fibrosis. Both mTORC1 and mTORC2 likely plays a role in pulmonary fibrosis although the exact contribution from each complex is not clear. Both the canonical (Smad) and non-canonical (non-Smad) pathways may drive ongoing lung fibrosis, including altering metabolism, epithelial to mesenchymal transition (EMT), inflammation, and proliferation. It is possible that different mechanisms are predominate within different cell types to promote fibrosis; for example, Smad-dependent TGF-β signaling may trigger apoptosis in lung epithelial cells yet pro-fibrotic signals predominate in fibroblasts.
Figure 7
Figure 7
Potential roles of mTORC1 and mTORC2 in the development of EMT. TGF-β is important for the transdifferentiation of epithelial cells into fibroblast or myofibroblast-like cells. The exact roles of each mTOR complex are not clear in pulmonary fibrosis, but it is possible that the non-canonical TGF-β pathway contributes to mTORC1 activation, which induces EMT in lung epithelial cells near the site of injury. mTORC2 activity is induced in some cells undergoing EMT and may help ensure progression through the process. Rapamycin (mTORC1 inhibition) is capable of reversing EMT in some cells, suggesting transdifferentiation is disrupted.
Figure 8
Figure 8
PI3K/AKT dependent autophagy regulation in IPF fibroblasts. The arrows indicates positive regulation while the symbol T indicates the inhibition of autophagy.
Figure 9
Figure 9
The mTOR-dependent metabolic pathway.
Figure 10
Figure 10
Proposed interaction between mTOR and the induction of SASP signals. Senescent pneumocytes may contribute to pro-inflammatory and pro-fibrotic signals, which further contribute to the development of pulmonary fibrosis through the loss of parenchymal cells and selection for improved fibroblast survival.
Figure 11
Figure 11
The role of mTORC1 and mTORC2 in the development and progression of idiopathic pulmonary fibrosis (IPF) and radiation-induced pulmonary fibrosis (RIPF). mTORC1 and mTORC2 are intricately involved in promoting mechanisms that favor activated lung fibroblast survival and relentless collagen production. mTORC1 inhibitors have been shown to modulate RIPF and bleomycin-induced pulmonary fibrosis, suggesting they may be effective mitigators in fibroproliferative lung disease. The arrows indicate positive regulation while T indicates the inhibition of the target molecule.

References

    1. Wynn T.A. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat. Rev. Immunol. 2004;4:583–594. doi: 10.1038/nri1412.
    1. Nanchahal J., Hinz B. Strategies to overcome the hurdles to treat fibrosis, a major unmet clinical need. Proc. Natl. Acad. Sci. USA. 2016;113:7291–7293. doi: 10.1073/pnas.1607896113.
    1. Rosenbloom J., Macarak E., Piera-Velazquez S., Jimenez S.A. Human fibrotic diseases: Current challenges in fibrosis research. Methods Mol. Biol. 2017;1627:1–23.
    1. Antoniou K.M., Tomassetti S., Tsitoura E., Vancheri C. Idiopathic pulmonary fibrosis and lung cancer: A clinical and pathogenesis update. Curr. Opin. Pulm. Med. 2015;21:626–633. doi: 10.1097/MCP.0000000000000217.
    1. Calio A., Lever V., Rossi A., Gilioli E., Brunelli M., Dubini A., Tomassetti S., Piciucchi S., Nottegar A., Rossi G., et al. Increased frequency of bronchiolar histotypes in lung carcinomas associated with idiopathic pulmonary fibrosis. Histopathology. 2017;71:725–735. doi: 10.1111/his.13269.
    1. Karampitsakos T., Tzilas V., Tringidou R., Steiropoulos P., Aidinis V., Papiris S.A., Bouros D., Tzouvelekis A. Lung cancer in patients with idiopathic pulmonary fibrosis. Pulm. Pharmacol. Ther. 2017;45:1–10. doi: 10.1016/j.pupt.2017.03.016.
    1. Li J., Yang M., Li P., Su Z., Gao P., Zhang J. Idiopathic pulmonary fibrosis will increase the risk of lung cancer. Chin. Med. J. (Engl.) 2014;127:3142–3149.
    1. Hutchinson J., Fogarty A., Hubbard R., McKeever T. Global incidence and mortality of idiopathic pulmonary fibrosis: A systematic review. Eur. Respir. J. 2015;46:795–806. doi: 10.1183/09031936.00185114.
    1. Miller K.D., Siegel R.L., Lin C.C., Mariotto A.B., Kramer J.L., Rowland J.H., Stein K.D., Alteri R., Jemal A. Cancer treatment and survivorship statistics, 2016. CA Cancer J. Clin. 2016;66:271–289. doi: 10.3322/caac.21349.
    1. Richeldi L., Collard H.R., Jones M.G. Idiopathic pulmonary fibrosis. Lancet. 2017;389:1941–1952. doi: 10.1016/S0140-6736(17)30866-8.
    1. American Thoracic Society. European Respiratory Society American thoracic society/european respiratory society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. This joint statement of the american thoracic society (ATS), and the european respiratory society (ERS) was adopted by the ats board of directors, June 2001 and by the ers executive committee, June 2001. Am. J. Respir. Crit. Care Med. 2002;165:277–304.
    1. King T.E., Jr., Bradford W.Z., Castro-Bernardini S., Fagan E.A., Glaspole I., Glassberg M.K., Gorina E., Hopkins P.M., Kardatzke D., Lancaster L., et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014;370:2083–2092. doi: 10.1056/NEJMoa1402582.
    1. Richeldi L., du Bois R.M., Raghu G., Azuma A., Brown K.K., Costabel U., Cottin V., Flaherty K.R., Hansell D.M., Inoue Y., et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014;370:2071–2082. doi: 10.1056/NEJMoa1402584.
    1. Taskar V.S., Coultas D.B. Is idiopathic pulmonary fibrosis an environmental disease? Proc. Am. Thorac. Soc. 2006;3:293–298. doi: 10.1513/pats.200512-131TK.
    1. Peljto A.L., Zhang Y., Fingerlin T.E., Ma S.F., Garcia J.G., Richards T.J., Silveira L.J., Lindell K.O., Steele M.P., Loyd J.E., et al. Association between the muc5b promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. JAMA. 2013;309:2232–2239. doi: 10.1001/jama.2013.5827.
    1. Baumgartner K.B., Samet J.M., Stidley C.A., Colby T.V., Waldron J.A. Cigarette smoking: A risk factor for idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 1997;155:242–248. doi: 10.1164/ajrccm.155.1.9001319.
    1. Gulati M., Redlich C.A. Asbestosis and environmental causes of usual interstitial pneumonia. Curr. Opin. Pulm. Med. 2015;21:193–200. doi: 10.1097/MCP.0000000000000144.
    1. Thannickal V.J., Lee D.Y., White E.S., Cui Z., Larios J.M., Chacon R., Horowitz J.C., Day R.M., Thomas P.E. Myofibroblast differentiation by transforming growth factor-β1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J. Biol. Chem. 2003;278:12384–12389. doi: 10.1074/jbc.M208544200.
    1. Zhang H.Y., Phan S.H. Inhibition of myofibroblast apoptosis by transforming growth factor β1. Am. J. Respir. Cell Mol. Biol. 1999;21:658–665. doi: 10.1165/ajrcmb.21.6.3720.
    1. Di Lullo G.A., Sweeney S.M., Korkko J., Ala-Kokko L., San Antonio J.D. Mapping the ligand-binding sites and disease-associated mutations on the most abundant protein in the human, type i collagen. J. Biol. Chem. 2002;277:4223–4231. doi: 10.1074/jbc.M110709200.
    1. Stefanovic B. Rna protein interactions governing expression of the most abundant protein in human body, type i collagen. Wiley Interdiscip. Rev. RNA. 2013;4:535–545. doi: 10.1002/wrna.1177.
    1. Horn M.A., Trafford A.W. Aging and the cardiac collagen matrix: Novel mediators of fibrotic remodelling. J. Mol. Cell. Cardiol. 2016;93:175–185. doi: 10.1016/j.yjmcc.2015.11.005.
    1. Tamura M., Gu J., Danen E.H., Takino T., Miyamoto S., Yamada K.M. Pten interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/AKT cell survival pathway. J. Biol. Chem. 1999;274:20693–20703. doi: 10.1074/jbc.274.29.20693.
    1. Nho R.S., Hergert P., Kahm J., Jessurun J., Henke C. Pathological alteration of FoxO3a activity promotes idiopathic pulmonary fibrosis fibroblast proliferation on type i collagen matrix. Am. J. Pathol. 2011;179:2420–2430. doi: 10.1016/j.ajpath.2011.07.020.
    1. Xia H., Diebold D., Nho R., Perlman D., Kleidon J., Kahm J., Avdulov S., Peterson M., Nerva J., Bitterman P., et al. Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis. J. Exp. Med. 2008;205:1659–1672. doi: 10.1084/jem.20080001.
    1. Xia H., Khalil W., Kahm J., Jessurun J., Kleidon J., Henke C.A. Pathologic caveolin-1 regulation of pten in idiopathic pulmonary fibrosis. Am. J. Pathol. 2010;176:2626–2637. doi: 10.2353/ajpath.2010.091117.
    1. Nho R.S., Peterson M., Hergert P., Henke C.A. FoxO3a (forkhead box O3a) deficiency protects idiopathic pulmonary fibrosis (ipf) fibroblasts from type i polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and fas. PLoS ONE. 2013;8:e61017. doi: 10.1371/journal.pone.0061017.
    1. DeVita V.T., Jr. Progress in cancer management. Keynote address. Cancer. 1983;51:2401–2409. doi: 10.1002/1097-0142(19830615)51:12+<2401::AID-CNCR2820511302>;2-7.
    1. Kong F.M., Hayman J.A., Griffith K.A., Kalemkerian G.P., Arenberg D., Lyons S., Turrisi A., Lichter A., Fraass B., Eisbruch A., et al. Final toxicity results of a radiation-dose escalation study in patients with non-small-cell lung cancer (nsclc): Predictors for radiation pneumonitis and fibrosis. Int. J. Radiat. Oncol. Biol. Phys. 2006;65:1075–1086. doi: 10.1016/j.ijrobp.2006.01.051.
    1. Stenmark M.H., Cai X.W., Shedden K., Hayman J.A., Yuan S., Ritter T., Ten Haken R.K., Lawrence T.S., Kong F.M. Combining physical and biologic parameters to predict radiation-induced lung toxicity in patients with non-small-cell lung cancer treated with definitive radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 2012;84:e217–e222. doi: 10.1016/j.ijrobp.2012.03.067.
    1. Barriger R.B., Forquer J.A., Brabham J.G., Andolino D.L., Shapiro R.H., Henderson M.A., Johnstone P.A., Fakiris A.J. A dose-volume analysis of radiation pneumonitis in non-small cell lung cancer patients treated with stereotactic body radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 2012;82:457–462. doi: 10.1016/j.ijrobp.2010.08.056.
    1. Ricardi U., Filippi A.R., Guarneri A., Giglioli F.R., Mantovani C., Fiandra C., Anglesio S., Ragona R. Dosimetric predictors of radiation-induced lung injury in stereotactic body radiation therapy. Acta Oncol. 2009;48:571–577. doi: 10.1080/02841860802520821.
    1. Trovo M., Minatel E., Durofil E., Polesel J., Avanzo M., Baresic T., Bearz A., Del Conte A., Franchin G., Gobitti C., et al. Stereotactic body radiation therapy for re-irradiation of persistent or recurrent non-small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 2014;88:1114–1119. doi: 10.1016/j.ijrobp.2014.01.012.
    1. Ueki N., Matsuo Y., Togashi Y., Kubo T., Shibuya K., Iizuka Y., Mizowaki T., Togashi K., Mishima M., Hiraoka M. Impact of pretreatment interstitial lung disease on radiation pneumonitis and survival after stereotactic body radiation therapy for lung cancer. J. Thorac. Oncol. 2015;10:116–125. doi: 10.1097/JTO.0000000000000359.
    1. Takeda A., Kunieda E., Takeda T., Tanaka M., Sanuki N., Fujii H., Shigematsu N., Kubo A. Possible misinterpretation of demarcated solid patterns of radiation fibrosis on ct scans as tumor recurrence in patients receiving hypofractionated stereotactic radiotherapy for lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 2008;70:1057–1065. doi: 10.1016/j.ijrobp.2007.07.2383.
    1. Yamashita H., Nakagawa K., Nakamura N., Koyanagi H., Tago M., Igaki H., Shiraishi K., Sasano N., Ohtomo K. Exceptionally high incidence of symptomatic grade 2–5 radiation pneumonitis after stereotactic radiation therapy for lung tumors. Radiat. Oncol. 2007;2:21. doi: 10.1186/1748-717X-2-21.
    1. Graves P.R., Siddiqui F., Anscher M.S., Movsas B. Radiation pulmonary toxicity: From mechanisms to management. Semin. Radiat. Oncol. 2010;20:201–207. doi: 10.1016/j.semradonc.2010.01.010.
    1. Williams J.P., Johnston C.J., Finkelstein J.N. Treatment for radiation-induced pulmonary late effects: Spoiled for choice or looking in the wrong direction? Curr. Drug Targets. 2010;11:1386–1394. doi: 10.2174/1389450111009011386.
    1. Brush J., Lipnick S.L., Phillips T., Sitko J., McDonald J.T., McBride W.H. Molecular mechanisms of late normal tissue injury. Semin. Radiat. Oncol. 2007;17:121–130. doi: 10.1016/j.semradonc.2006.11.008.
    1. Abratt R.P., Morgan G.W. Lung toxicity following chest irradiation in patients with lung cancer. Lung Cancer. 2002;35:103–109. doi: 10.1016/S0169-5002(01)00334-8.
    1. Zhang X.J., Sun J.G., Sun J., Ming H., Wang X.X., Wu L., Chen Z.T. Prediction of radiation pneumonitis in lung cancer patients: A systematic review. J. Cancer Res. Clin. Oncol. 2012;138:2103–2116. doi: 10.1007/s00432-012-1284-1.
    1. Rodrigues G., Lock M., D’Souza D., Yu E., Van Dyk J. Prediction of radiation pneumonitis by dose-volume histogram parameters in lung cancer—A systematic review. Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol. 2004;71:127–138. doi: 10.1016/j.radonc.2004.02.015.
    1. Tsujino K., Hashimoto T., Shimada T., Yoden E., Fujii O., Ota Y., Satouchi M., Negoro S., Adachi S., Soejima T. Combined analysis of v20, vs5, pulmonary fibrosis score on baseline computed tomography, and patient age improves prediction of severe radiation pneumonitis after concurrent chemoradiotherapy for locally advanced non-small-cell lung cancer. J. Thorac. Oncol. 2014;9:983–990. doi: 10.1097/JTO.0000000000000187.
    1. Ozawa Y., Abe T., Omae M., Matsui T., Kato M., Hasegawa H., Enomoto Y., Ishihara T., Inui N., Yamada K., et al. Impact of preexisting interstitial lung disease on acute, extensive radiation pneumonitis: Retrospective analysis of patients with lung cancer. PLoS ONE. 2015;10:e0140437. doi: 10.1371/journal.pone.0140437.
    1. Mehta V. Radiation pneumonitis and pulmonary fibrosis in non-small-cell lung cancer: Pulmonary function, prediction, and prevention. Int. J. Radiat. Oncol. Biol. Phys. 2005;63:5–24. doi: 10.1016/j.ijrobp.2005.03.047.
    1. Citrin D.E., Prasanna P.G.S., Walker A.J., Freeman M.L., Eke I., Barcellos-Hoff M.H., Arankalayil M.J., Cohen E.P., Wilkins R.C., Ahmed M.M., et al. Radiation-induced fibrosis: Mechanisms and opportunities to mitigate. Report of an nci workshop, september 19, 2016. Radiat. Res. 2017;188:1–20. doi: 10.1667/RR14784.1.
    1. Morgan G.W., Breit S.N. Radiation and the lung: A reevaluation of the mechanisms mediating pulmonary injury. Int. J. Radiat. Oncol. Biol. Phys. 1995;31:361–369. doi: 10.1016/0360-3016(94)00477-3.
    1. Wynn T.A. Cellular and molecular mechanisms of fibrosis. J. Pathol. 2008;214:199–210. doi: 10.1002/path.2277.
    1. Wynn T.A. Integrating mechanisms of pulmonary fibrosis. J. Exp. Med. 2011;208:1339–1350. doi: 10.1084/jem.20110551.
    1. Vallee A., Lecarpentier Y., Guillevin R., Vallee J.N. Interactions between TGF-beta1, canonical WNT/beta-catenin pathway and ppar gamma in radiation-induced fibrosis. Oncotarget. 2017;8:90579–90604. doi: 10.18632/oncotarget.21234.
    1. Rube C.E., Uthe D., Schmid K.W., Richter K.D., Wessel J., Schuck A., Willich N., Rube C. Dose-dependent induction of transforming growth factor beta (Tgf-beta) in the lung tissue of fibrosis-prone mice after thoracic irradiation. Int. J. Radiat. Oncol. Biol. Phys. 2000;47:1033–1042. doi: 10.1016/S0360-3016(00)00482-X.
    1. Almeida C., Nagarajan D., Tian J., Leal S.W., Wheeler K., Munley M., Blackstock W., Zhao W. The role of alveolar epithelium in radiation-induced lung injury. PLoS ONE. 2013;8:e53628. doi: 10.1371/journal.pone.0053628.
    1. Rubin P., Johnston C.J., Williams J.P., McDonald S., Finkelstein J.N. A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis. Int. J. Radiat. Oncol. Biol. Phys. 1995;33:99–109. doi: 10.1016/0360-3016(95)00095-G.
    1. Citrin D.E., Mitchell J.B. Mechanisms of normal tissue injury from irradiation. Semin. Radiat. Oncol. 2017;27:316–324. doi: 10.1016/j.semradonc.2017.04.001.
    1. Kim K.K., Kugler M.C., Wolters P.J., Robillard L., Galvez M.G., Brumwell A.N., Sheppard D., Chapman H.A. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc. Natl. Acad. Sci. USA. 2006;103:13180–13185. doi: 10.1073/pnas.0605669103.
    1. Sahlgren C., Gustafsson M.V., Jin S., Poellinger L., Lendahl U. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc. Natl. Acad. Sci. USA. 2008;105:6392–6397. doi: 10.1073/pnas.0802047105.
    1. Kalluri R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer. 2016;16:582–598. doi: 10.1038/nrc.2016.73.
    1. Guo B., Yan H., Li L., Yin K., Ji F., Zhang S. Collagen triple helix repeat containing 1 (CTHRC1) activates integrin beta3/FAK signaling and promotes metastasis in ovarian cancer. J. Ovarian Res. 2017;10:69. doi: 10.1186/s13048-017-0358-8.
    1. Yu Y., Xiao C.H., Tan L.D., Wang Q.S., Li X.Q., Feng Y.M. Cancer-associated fibroblasts induce epithelial-mesenchymal transition of breast cancer cells through paracrine TGF-beta signalling. Br. J. Cancer. 2014;110:724–732. doi: 10.1038/bjc.2013.768.
    1. Harper J., Sainson R.C. Regulation of the anti-tumour immune response by cancer-associated fibroblasts. Semin. Cancer Biol. 2014;25:69–77. doi: 10.1016/j.semcancer.2013.12.005.
    1. Santi A., Kugeratski F.G., Zanivan S. Cancer associated fibroblasts: The architects of stroma remodelling. Proteomics. 2017 doi: 10.1002/pmic.201700167.
    1. Cirri P., Chiarugi P. Cancer-associated-fibroblasts and tumour cells: A diabolic liaison driving cancer progression. Cancer Metastasis Rev. 2012;31:195–208. doi: 10.1007/s10555-011-9340-x.
    1. Polanska U.M., Orimo A. Carcinoma-associated fibroblasts: Non-neoplastic tumour-promoting mesenchymal cells. J. Cell. Physiol. 2013;228:1651–1657. doi: 10.1002/jcp.24347.
    1. Catalano V., Turdo A., Di Franco S., Dieli F., Todaro M., Stassi G. Tumor and its microenvironment: A synergistic interplay. Semin. Cancer Biol. 2013;23:522–532. doi: 10.1016/j.semcancer.2013.08.007.
    1. Khalil A., Morgan R.N., Adams B.R., Golding S.E., Dever S.M., Rosenberg E., Povirk L.F., Valerie K. ATM-dependent ERK signaling via AKT in response to DNA double-strand breaks. Cell Cycle. 2011;10:481–491. doi: 10.4161/cc.10.3.14713.
    1. Valerie K., Povirk L.F. Regulation and mechanisms of mammalian double-strand break repair. Oncogene. 2003;22:5792–5812. doi: 10.1038/sj.onc.1206679.
    1. Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R., 3rd, Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., et al. Atm and atr substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 2007;316:1160–1166. doi: 10.1126/science.1140321.
    1. Engelman J.A., Luo J., Cantley L.C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 2006;7:606–619. doi: 10.1038/nrg1879.
    1. Janku F. Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: From laboratory to patients. Cancer Treat. Rev. 2017;59:93–101. doi: 10.1016/j.ctrv.2017.07.005.
    1. Malemud C.J. The PI3K/AKT/PTEN/mTOR pathway: A fruitful target for inducing cell death in rheumatoid arthritis? Future Med. Chem. 2015;7:1137–1147. doi: 10.4155/fmc.15.55.
    1. Wander S.A., Hennessy B.T., Slingerland J.M. Next-generation mTOR inhibitors in clinical oncology: How pathway complexity informs therapeutic strategy. J. Clin. Investig. 2011;121:1231–1241. doi: 10.1172/JCI44145.
    1. Chung E.J., Sowers A., Thetford A., McKay-Corkum G., Chung S.I., Mitchell J.B., Citrin D.E. Mammalian target of rapamycin inhibition with rapamycin mitigates radiation-induced pulmonary fibrosis in a murine model. Int. J. Radiat. Oncol. Biol. Phys. 2016;96:857–866. doi: 10.1016/j.ijrobp.2016.07.026.
    1. Citrin D.E., Shankavaram U., Horton J.A., Shield W., 3rd, Zhao S., Asano H., White A., Sowers A., Thetford A., Chung E.J. Role of type ii pneumocyte senescence in radiation-induced lung fibrosis. J. Natl. Cancer Inst. 2013;105:1474–1484. doi: 10.1093/jnci/djt212.
    1. Rahimi R.A., Andrianifahanana M., Wilkes M.C., Edens M., Kottom T.J., Blenis J., Leof E.B. Distinct roles for mammalian target of rapamycin complexes in the fibroblast response to transforming growth factor-beta. Cancer Res. 2009;69:84–93. doi: 10.1158/0008-5472.CAN-08-2146.
    1. Chung J., Kuo C.J., Crabtree G.R., Blenis J. Rapamycin-fkbp specifically blocks growth-dependent activation of and signaling by the 70 kd s6 protein kinases. Cell. 1992;69:1227–1236. doi: 10.1016/0092-8674(92)90643-Q.
    1. Kuo C.J., Chung J., Fiorentino D.F., Flanagan W.M., Blenis J., Crabtree G.R. Rapamycin selectively inhibits interleukin-2 activation of p70 s6 kinase. Nature. 1992;358:70–73. doi: 10.1038/358070a0.
    1. Laplante M., Sabatini D.M. Mtor signaling in growth control and disease. Cell. 2012;149:274–293. doi: 10.1016/j.cell.2012.03.017.
    1. Saxton R.A., Sabatini D.M. Mtor signaling in growth, metabolism, and disease. Cell. 2017;168:960–976. doi: 10.1016/j.cell.2017.02.004.
    1. Feng J., Liao Y., Xu X., Yi Q., He L., Tang L. HnRNP A1 promotes keratinocyte cell survival post UVB radiation through PI3K/AKT/mTOR pathway. Exp. Cell Res. 2017;362:394–399. doi: 10.1016/j.yexcr.2017.12.002.
    1. Sarbassov D.D., Ali S.M., Sengupta S., Sheen J.H., Hsu P.P., Bagley A.F., Markhard A.L., Sabatini D.M. Prolonged rapamycin treatment inhibits mTORC2 assembly and AKT/PKB. Mol. Cell. 2006;22:159–168. doi: 10.1016/j.molcel.2006.03.029.
    1. Huang J., Manning B.D. The TSC1-TSC2 complex: A molecular switchboard controlling cell growth. Biochem. J. 2008;412:179–190. doi: 10.1042/BJ20080281.
    1. Zinzalla V., Stracka D., Oppliger W., Hall M.N. Activation of mTORC2 by association with the ribosome. Cell. 2011;144:757–768. doi: 10.1016/j.cell.2011.02.014.
    1. Huang J., Manning B.D. A complex interplay between AKT, TSC2 and the two mTOR complexes. Biochem. Soc. Trans. 2009;37:217–222. doi: 10.1042/BST0370217.
    1. Huang Z., Wu Y., Zhou X., Qian J., Zhu W., Shu Y., Liu P. Clinical efficacy of mTOR inhibitors in solid tumors: A systematic review. Future Oncol. 2015;11:1687–1699. doi: 10.2217/fon.15.70.
    1. Lazo J.S., Sharlow E.R., Epperly M.W., Lira A., Leimgruber S., Skoda E.M., Wipf P., Greenberger J.S. Pharmacologic profiling of phosphoinositide 3-kinase inhibitors as mitigators of ionizing radiation-induced cell death. J. Pharmacol. Exp. Ther. 2013;347:669–680. doi: 10.1124/jpet.113.208421.
    1. Moschetta M., Reale A., Marasco C., Vacca A., Carratu M.R. Therapeutic targeting of the mTOR-signalling pathway in cancer: Benefits and limitations. Br. J. Pharmacol. 2014;171:3801–3813. doi: 10.1111/bph.12749.
    1. Walker N.M., Belloli E.A., Stuckey L., Chan K.M., Lin J., Lynch W., Chang A., Mazzoni S.M., Fingar D.C., Lama V.N. Mechanistic target of rapamycin Complex 1 (mTORC1) and mTORC2 as key signaling intermediates in mesenchymal cell activation. J. Biol. Chem. 2016;291:6262–6271. doi: 10.1074/jbc.M115.672170.
    1. Nojima H., Tokunaga C., Eguchi S., Oshiro N., Hidayat S., Yoshino K., Hara K., Tanaka N., Avruch J., Yonezawa K. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 s6 kinase and 4E-BP1 through their tor signaling (TOS) motif. J. Biol. Chem. 2003;278:15461–15464. doi: 10.1074/jbc.C200665200.
    1. Schalm S.S., Fingar D.C., Sabatini D.M., Blenis J. Tos motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr. Biol. 2003;13:797–806. doi: 10.1016/S0960-9822(03)00329-4.
    1. Yang H., Rudge D.G., Koos J.D., Vaidialingam B., Yang H.J., Pavletich N.P. Mtor kinase structure, mechanism and regulation. Nature. 2013;497:217–223. doi: 10.1038/nature12122.
    1. Peterson T.R., Laplante M., Thoreen C.C., Sancak Y., Kang S.A., Kuehl W.M., Gray N.S., Sabatini D.M. Deptor is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137:873–886. doi: 10.1016/j.cell.2009.03.046.
    1. Sancak Y., Thoreen C.C., Peterson T.R., Lindquist R.A., Kang S.A., Spooner E., Carr S.A., Sabatini D.M. Pras40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell. 2007;25:903–915. doi: 10.1016/j.molcel.2007.03.003.
    1. Wang L., Harris T.E., Roth R.A., Lawrence J.C., Jr. Pras40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J. Biol. Chem. 2007;282:20036–20044. doi: 10.1074/jbc.M702376200.
    1. Soares J.A., Leite F.G., Andrade L.G., Torres A.A., De Sousa L.P., Barcelos L.S., Teixeira M.M., Ferreira P.C., Kroon E.G., Souto-Padron T., et al. Activation of the PI3K/AKT pathway early during vaccinia and cowpox virus infections is required for both host survival and viral replication. J. Virol. 2009;83:6883–6899. doi: 10.1128/JVI.00245-09.
    1. Chang W., Wei K., Ho L., Berry G.J., Jacobs S.S., Chang C.H., Rosen G.D. A critical role for the mTORC2 pathway in lung fibrosis. PLoS ONE. 2014;9:e106155. doi: 10.1371/journal.pone.0106155.
    1. Hsu P.P., Kang S.A., Rameseder J., Zhang Y., Ottina K.A., Lim D., Peterson T.R., Choi Y., Gray N.S., Yaffe M.B., et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science. 2011;332:1317–1322. doi: 10.1126/science.1199498.
    1. Yu Y., Yoon S.O., Poulogiannis G., Yang Q., Ma X.M., Villen J., Kubica N., Hoffman G.R., Cantley L.C., Gygi S.P., et al. Phosphoproteomic analysis identifies grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science. 2011;332:1322–1326. doi: 10.1126/science.1199484.
    1. Harrington L.S., Findlay G.M., Gray A., Tolkacheva T., Wigfield S., Rebholz H., Barnett J., Leslie N.R., Cheng S., Shepherd P.R., et al. The TSC1-2 tumor suppressor controls insulin—PI3K signaling via regulation of IRS proteins. J. Cell Biol. 2004;166:213–223. doi: 10.1083/jcb.200403069.
    1. Shah O.J., Wang Z., Hunter T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr. Biol. 2004;14:1650–1656. doi: 10.1016/j.cub.2004.08.026.
    1. Nasmyth K. Retinoblastoma protein. Another role rolls in. Nature. 1996;382:28–29. doi: 10.1038/382028a0.
    1. Cope C.L., Gilley R., Balmanno K., Sale M.J., Howarth K.D., Hampson M., Smith P.D., Guichard S.M., Cook S.J. Adaptation to mTOR kinase inhibitors by amplification of eif4e to maintain cap-dependent translation. J. Cell Sci. 2014;127:788–800. doi: 10.1242/jcs.137588.
    1. Lopez-Rivera E., Jayaraman P., Parikh F., Davies M.A., Ekmekcioglu S., Izadmehr S., Milton D.R., Chipuk J.E., Grimm E.A., Estrada Y., et al. Inducible nitric oxide synthase drives mTOR pathway activation and proliferation of human melanoma by reversible nitrosylation of tsc2. Cancer Res. 2014;74:1067–1078. doi: 10.1158/0008-5472.CAN-13-0588.
    1. Jung F., Haendeler J., Goebel C., Zeiher A.M., Dimmeler S. Growth factor-induced phosphoinositide 3-OH kinase/AKT phosphorylation in smooth muscle cells: Induction of cell proliferation and inhibition of cell death. Cardiovasc. Res. 2000;48:148–157. doi: 10.1016/S0008-6363(00)00152-8.
    1. Shelton J.G., Moye P.W., Steelman L.S., Blalock W.L., Lee J.T., Franklin R.A., McMahon M., McCubrey J.A. Differential effects of kinase cascade inhibitors on neoplastic and cytokine-mediated cell proliferation. Leukemia. 2003;17:1765–1782. doi: 10.1038/sj.leu.2403052.
    1. Gao N., Flynn D.C., Zhang Z., Zhong X.S., Walker V., Liu K.J., Shi X., Jiang B.H. G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70s6k1 signaling in human ovarian cancer cells. Am. J. Physiol. Cell Physiol. 2004;287:C281–C291. doi: 10.1152/ajpcell.00422.2003.
    1. Shelton J.G., Blalock W.L., White E.R., Steelman L.S., McCubrey J.A. Ability of the activated PI3K/AKT oncoproteins to synergize with MEK1 and induce cell cycle progression and abrogate the cytokine-dependence of hematopoietic cells. Cell Cycle. 2004;3:503–512. doi: 10.4161/cc.3.4.813.
    1. Horn S., Bergholz U., Jucker M., McCubrey J.A., Trumper L., Stocking C., Basecke J. Mutations in the catalytic subunit of class ia PI3K confer leukemogenic potential to hematopoietic cells. Oncogene. 2008;27:4096–4106. doi: 10.1038/onc.2008.40.
    1. Zhao L., Vogt P.K. Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc. Natl. Acad. Sci. USA. 2008;105:2652–2657. doi: 10.1073/pnas.0712169105.
    1. Bader A.G., Kang S., Zhao L., Vogt P.K. Oncogenic PI3K deregulates transcription and translation. Nat. Rev. Cancer. 2005;5:921–929. doi: 10.1038/nrc1753.
    1. Parker V.E., Knox R.G., Zhang Q., Wakelam M.J., Semple R.K. Phosphoinositide 3-kinase-related overgrowth: Cellular phenotype and future therapeutic options. Lancet. 2015;385(Suppl. S1) doi: 10.1016/S0140-6736(15)60392-0.
    1. Das F., Ghosh-Choudhury N., Mariappan M.M., Kasinath B.S., Choudhury G.G. Hydrophobic motif site-phosphorylated protein kinase cbetaii between mTORC2 and akt regulates high glucose-induced mesangial cell hypertrophy. Am. J. Physiol. Cell Physiol. 2016;310:C583–C596. doi: 10.1152/ajpcell.00266.2015.
    1. Hsu H.S., Liu C.C., Lin J.H., Hsu T.W., Hsu J.W., Su K., Hung S.C. Involvement of er stress, PI3K/AKT activation, and lung fibroblast proliferation in bleomycin-induced pulmonary fibrosis. Sci. Rep. 2017;7:14272. doi: 10.1038/s41598-017-14612-5.
    1. Syed F., Sherris D., Paus R., Varmeh S., Singh S., Pandolfi P.P., Bayat A. Keloid disease can be inhibited by antagonizing excessive mTOR signaling with a novel dual torc1/2 inhibitor. Am. J. Pathol. 2012;181:1642–1658. doi: 10.1016/j.ajpath.2012.08.006.
    1. Sarbassov D.D., Guertin D.A., Ali S.M., Sabatini D.M. Phosphorylation and regulation of AKT/PKB by the rictor-mTOR complex. Science. 2005;307:1098–1101. doi: 10.1126/science.1106148.
    1. Palm W., Park Y., Wright K., Pavlova N.N., Tuveson D.A., Thompson C.B. The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell. 2015;162:259–270. doi: 10.1016/j.cell.2015.06.017.
    1. Nho R.S., Hergert P. Ipf fibroblasts are desensitized to type i collagen matrix-induced cell death by suppressing low autophagy via aberrant AKT/mTOR kinases. PLoS ONE. 2014;9:e94616. doi: 10.1371/journal.pone.0094616.
    1. Strimpakos A.S., Karapanagiotou E.M., Saif M.W., Syrigos K.N. The role of mTOR in the management of solid tumors: An overview. Cancer Treat. Rev. 2009;35:148–159. doi: 10.1016/j.ctrv.2008.09.006.
    1. Wang D., Gao L., Liu X., Yuan C., Wang G. Improved antitumor effect of ionizing radiation in combination with rapamycin for treating nasopharyngeal carcinoma. Oncol. Lett. 2017;14:1105–1108. doi: 10.3892/ol.2017.6208.
    1. Miyahara H., Yadavilli S., Natsumeda M., Rubens J.A., Rodgers L., Kambhampati M., Taylor I.C., Kaur H., Asnaghi L., Eberhart C.G., et al. The dual mTOR kinase inhibitor tak228 inhibits tumorigenicity and enhances radiosensitization in diffuse intrinsic pontine glioma. Cancer Lett. 2017;400:110–116. doi: 10.1016/j.canlet.2017.04.019.
    1. Eke I., Makinde A.Y., Aryankalayil M.J., Sandfort V., Palayoor S.T., Rath B.H., Liotta L., Pierobon M., Petricoin E.F., Brown M.F., et al. Exploiting radiation-induced signaling to increase the susceptibility of resistant cancer cells to targeted drugs: AKT and mTOR inhibitors as an example. Mol. Cancer Ther. 2017;17:355–367. doi: 10.1158/1535-7163.MCT-17-0262.
    1. Nagata Y., Takahashi A., Ohnishi K., Ota I., Ohnishi T., Tojo T., Taniguchi S. Effect of rapamycin, an mTOR inhibitor, on radiation sensitivity of lung cancer cells having different p53 gene status. Int. J. Oncol. 2010;37:1001–1010. doi: 10.3892/ijo_00000751.
    1. Dumont F.J., Bischoff P. Disrupting the mTOR signaling network as a potential strategy for the enhancement of cancer radiotherapy. Curr. Cancer Drug Targets. 2012;12:899–924. doi: 10.2174/156800912803251243.
    1. Sharlow E.R., Leimgruber S., Lira A., McConnell M.J., Norambuena A., Bloom G.S., Epperly M.W., Greenberger J.S., Lazo J.S. A small molecule screen exposes mTOR signaling pathway involvement in radiation-induced apoptosis. ACS Chem. Biol. 2016;11:1428–1437. doi: 10.1021/acschembio.5b00909.
    1. Iglesias-Bartolome R., Patel V., Cotrim A., Leelahavanichkul K., Molinolo A.A., Mitchell J.B., Gutkind J.S. Mtor inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis. Cell Stem Cell. 2012;11:401–414. doi: 10.1016/j.stem.2012.06.007.
    1. Betz C., Hall M.N. Where is mTOR and what is it doing there? J. Cell Biol. 2013;203:563–574. doi: 10.1083/jcb.201306041.
    1. Wang Y., Yamada E., Zong H., Pessin J.E. Fyn activation of mTORC1 stimulates the ire1alpha-JNK pathway, leading to cell death. J. Biol. Chem. 2015;290:24772–24783. doi: 10.1074/jbc.M115.687020.
    1. Feng Z., Hu W., de Stanchina E., Teresky A.K., Jin S., Lowe S., Levine A.J. The regulation of AMPK beta1, tsc2, and pten expression by p53: Stress, cell and tissue specificity, and the role of these gene products in modulating the igf-1-AKT-mTOR pathways. Cancer Res. 2007;67:3043–3053. doi: 10.1158/0008-5472.CAN-06-4149.
    1. Feng Z., Zhang H., Levine A.J., Jin S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc. Natl. Acad. Sci. USA. 2005;102:8204–8209. doi: 10.1073/pnas.0502857102.
    1. Jhanwar-Uniyal M., Gillick J.L., Neil J., Tobias M., Thwing Z.E., Murali R. Distinct signaling mechanisms of mTORC1 and mTORC2 in glioblastoma multiforme: A tale of two complexes. Adv. Biol. Regul. 2015;57:64–74. doi: 10.1016/j.jbior.2014.09.004.
    1. Hayman T.J., Wahba A., Rath B.H., Bae H., Kramp T., Shankavaram U.T., Camphausen K., Tofilon P.J. The ATP-competitive mTOR inhibitor INK128 enhances in vitro and in vivo radiosensitivity of pancreatic carcinoma cells. Clin. Cancer Res. 2014;20:110–119. doi: 10.1158/1078-0432.CCR-13-2136.
    1. Liu Z.G., Tang J., Chen Z., Zhang H., Wang H., Yang J., Zhang H. The novel mTORC1/2 dual inhibitor ink128 enhances radiosensitivity of breast cancer cell line MCF-7. Int. J. Oncol. 2016;49:1039–1045. doi: 10.3892/ijo.2016.3604.
    1. Zellefrow C.D., Sharlow E.R., Epperly M.W., Reese C.E., Shun T., Lira A., Greenberger J.S., Lazo J.S. Identification of druggable targets for radiation mitigation using a small interfering rna screening assay. Radiat. Res. 2012;178:150–159. doi: 10.1667/RR2810.1.
    1. Willers H., Held K.D. Introduction to clinical radiation biology. Hematol. Oncol. Clin. N. Am. 2006;20:1–24. doi: 10.1016/j.hoc.2006.01.007.
    1. Powell S., McMillan T.J. DNA damage and repair following treatment with ionizing radiation. Radiother. Oncol. 1990;19:95–108. doi: 10.1016/0167-8140(90)90123-E.
    1. Wang W.H., Chien T.H., Fan S.M., Huang W.Y., Lai S.F., Wu J.T., Lin S.J. Activation of mTORC1 signaling is required for timely hair follicle regeneration from radiation injury. Radiat. Res. 2017;188:681–689. doi: 10.1667/RR14830.1.
    1. Xia H., Nho R.S., Kahm J., Kleidon J., Henke C.A. Focal adhesion kinase is upstream of phosphatidylinositol 3-Kinase/AKT in regulating fibroblast survival in response to contraction of type i collagen matrices via a beta 1 integrin viability signaling pathway. J. Biol. Chem. 2004;279:33024–33034. doi: 10.1074/jbc.M313265200.
    1. Udayakumar D., Pandita R.K., Horikoshi N., Liu Y., Liu Q., Wong K.K., Hunt C.R., Gray N.S., Minna J.D., Pandita T.K., et al. Torin2 suppresses ionizing radiation-induced DNA damage repair. Radiat. Res. 2016;185:527–538. doi: 10.1667/RR14373.1.
    1. Beuvink I., Boulay A., Fumagalli S., Zilbermann F., Ruetz S., O’Reilly T., Natt F., Hall J., Lane H.A., Thomas G. The mTOR inhibitor rad001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell. 2005;120:747–759. doi: 10.1016/j.cell.2004.12.040.
    1. Selvarajah J., Elia A., Carroll V.A., Moumen A. DNA damage-induced s and g2/m cell cycle arrest requires mTORC2-dependent regulation of chk1. Oncotarget. 2015;6:427–440. doi: 10.18632/oncotarget.2813.
    1. Albert J.M., Kim K.W., Cao C., Lu B. Targeting the AKT/mammalian target of rapamycin pathway for radiosensitization of breast cancer. Mol. Cancer Ther. 2006;5:1183–1189. doi: 10.1158/1535-7163.MCT-05-0400.
    1. Silvera D., Ernlund A., Arju R., Connolly E., Volta V., Wang J., Schneider R.J. MTORC1 and -2 coordinate transcriptional and translational reprogramming in resistance to DNA damage and replicative stress in breast cancer cells. Mol. Cell. Biol. 2017;37:e00577-16. doi: 10.1128/MCB.00577-16.
    1. Eriksson D., Lofroth P.O., Johansson L., Riklund K.A., Stigbrand T. Cell cycle disturbances and mitotic catastrophes in HeLa Hep2 cells following 2.5 to 10 gy of ionizing radiation. Clin. Cancer Res. 2007;13:5501s–5508s. doi: 10.1158/1078-0432.CCR-07-0980.
    1. Castedo M., Perfettini J.L., Roumier T., Valent A., Raslova H., Yakushijin K., Horne D., Feunteun J., Lenoir G., Medema R., et al. Mitotic catastrophe constitutes a special case of apoptosis whose suppression entails aneuploidy. Oncogene. 2004;23:4362–4370. doi: 10.1038/sj.onc.1207572.
    1. Castedo M., Perfettini J.L., Roumier T., Andreau K., Medema R., Kroemer G. Cell death by mitotic catastrophe: A molecular definition. Oncogene. 2004;23:2825–2837. doi: 10.1038/sj.onc.1207528.
    1. Eriksson D., Stigbrand T. Radiation-induced cell death mechanisms. Tumour Biol. 2010;31:363–372. doi: 10.1007/s13277-010-0042-8.
    1. Eriksson D., Lofroth P.O., Johansson L., Riklund K., Stigbrand T. Apoptotic signalling in HeLa Hep2 cells following 5 Gy of cobalt-60 gamma radiation. Anticancer Res. 2009;29:4361–4366.
    1. Hall E.J., Giaccia A.J. Radiobiology for the Radiologis. 7th ed. Lippincott Williams & Wilkins; Philadelphia, PA, USA: 2011.
    1. Im-aram A., Farrand L., Bae S.M., Song G., Song Y.S., Han J.Y., Tsang B.K. The mTORC2 component rictor contributes to cisplatin resistance in human ovarian cancer cells. PLoS ONE. 2013;8:e75455. doi: 10.1371/journal.pone.0075455.
    1. Liu H., Zang C., Schefe J.H., Schwarzlose-Schwarck S., Regierer A.C., Elstner E., Schulz C.O., Scholz C., Possinger K., Eucker J. The mTOR inhibitor rad001 sensitizes tumor cells to the cytotoxic effect of carboplatin in breast cancer in vitro. Anticancer Res. 2011;31:2713–2722.
    1. Liu H., Scholz C., Zang C., Schefe J.H., Habbel P., Regierer A.C., Schulz C.O., Possinger K., Eucker J. Metformin and the mTOR inhibitor everolimus (rad001) sensitize breast cancer cells to the cytotoxic effect of chemotherapeutic drugs in vitro. Anticancer Res. 2012;32:1627–1637.
    1. Budanov A.V., Karin M. P53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell. 2008;134:451–460. doi: 10.1016/j.cell.2008.06.028.
    1. Guo F., Li J., Du W., Zhang S., O’Connor M., Thomas G., Kozma S., Zingarelli B., Pang Q., Zheng Y. Mtor regulates DNA damage response through nf-kappab-mediated FANCD2 pathway in hematopoietic cells. Leukemia. 2013;27:2040–2046. doi: 10.1038/leu.2013.93.
    1. Shen C., Oswald D., Phelps D., Cam H., Pelloski C.E., Pang Q., Houghton P.J. Regulation of FANCD2 by the mTOR pathway contributes to the resistance of cancer cells to DNA double-strand breaks. Cancer Res. 2013;73:3393–3401. doi: 10.1158/0008-5472.CAN-12-4282.
    1. Abaji C., Cousineau I., Belmaaza A. Brca2 regulates homologous recombination in response to DNA damage: Implications for genome stability and carcinogenesis. Cancer Res. 2005;65:4117–4125. doi: 10.1158/0008-5472.CAN-04-3071.
    1. Luo K., Li L., Li Y., Wu C., Yin Y., Chen Y., Deng M., Nowsheen S., Yuan J., Lou Z. A phosphorylation-deubiquitination cascade regulates the brca2-rad51 axis in homologous recombination. Genes Dev. 2016;30:2581–2595. doi: 10.1101/gad.289439.116.
    1. Nestal de Moraes G., Bella L., Zona S., Burton M.J., Lam E.W. Insights into a critical role of the FOXO3a-FOXM1 axis in DNA damage response and genotoxic drug resistance. Curr. Drug Targets. 2016;17:164–177. doi: 10.2174/1389450115666141122211549.
    1. Tan Y., Raychaudhuri P., Costa R.H. Chk2 mediates stabilization of the foxm1 transcription factor to stimulate expression of DNA repair genes. Mol. Cell. Biol. 2007;27:1007–1016. doi: 10.1128/MCB.01068-06.
    1. Balli D., Ustiyan V., Zhang Y., Wang I.C., Masino A.J., Ren X., Whitsett J.A., Kalinichenko V.V., Kalin T.V. Foxm1 transcription factor is required for lung fibrosis and epithelial-to-mesenchymal transition. EMBO J. 2013;32:231–244. doi: 10.1038/emboj.2012.336.
    1. Karadedou C.T., Gomes A.R., Chen J., Petkovic M., Ho K.K., Zwolinska A.K., Feltes A., Wong S.Y., Chan K.Y., Cheung Y.N., et al. FoxO3a represses vegf expression through foxm1-dependent and -independent mechanisms in breast cancer. Oncogene. 2012;31:1845–1858. doi: 10.1038/onc.2011.368.
    1. Nho R.S., Im J., Ho Y.Y., Hergert P. Microrna-96 inhibits FoxO3a function in ipf fibroblasts on type i collagen matrix. Am. J. Physiol. Lung Cell. Mol. Physiol. 2014;307:L632–L642. doi: 10.1152/ajplung.00127.2014.
    1. Im J., Hergert P., Nho R.S. Reduced FoxO3a expression causes low autophagy in idiopathic pulmonary fibrosis fibroblasts on collagen matrices. Am. J. Physiol. Lung Cell. Mol. Physiol. 2015;309:L552–L561. doi: 10.1152/ajplung.00079.2015.
    1. Calveley V.L., Khan M.A., Yeung I.W., Vandyk J., Hill R.P. Partial volume rat lung irradiation: Temporal fluctuations of in-field and out-of-field DNA damage and inflammatory cytokines following irradiation. Int. J. Radiat. Biol. 2005;81:887–899. doi: 10.1080/09553000600568002.
    1. Rube C.E., Wilfert F., Palm J., Konig J., Burdak-Rothkamm S., Liu L., Schuck A., Willich N., Rube C. Irradiation induces a biphasic expression of pro-inflammatory cytokines in the lung. Strahlenther. Onkol. 2004;180:442–448. doi: 10.1007/s00066-004-1265-7.
    1. Herskind C., Bamberg M., Rodemann H.P. The role of cytokines in the development of normal-tissue reactions after radiotherapy. Strahlenther. Onkol. 1998;174(Suppl. S3):12–15.
    1. Willis B.C., Liebler J.M., Luby-Phelps K., Nicholson A.G., Crandall E.D., du Bois R.M., Borok Z. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: Potential role in idiopathic pulmonary fibrosis. Am. J. Pathol. 2005;166:1321–1332. doi: 10.1016/S0002-9440(10)62351-6.
    1. Papiris S.A., Tomos I.P., Karakatsani A., Spathis A., Korbila I., Analitis A., Kolilekas L., Kagouridis K., Loukides S., Karakitsos P., et al. High levels of IL-6 and IL-8 characterize early-on idiopathic pulmonary fibrosis acute exacerbations. Cytokine. 2017;102:168–172. doi: 10.1016/j.cyto.2017.08.019.
    1. Gonzalez-Gonzalez F.J., Chandel N.S., Jain M., Budinger G.R.S. Reactive oxygen species as signaling molecules in the development of lung fibrosis. Transl. Res. 2017;190:61–68. doi: 10.1016/j.trsl.2017.09.005.
    1. Koli K., Myllarniemi M., Keski-Oja J., Kinnula V.L. Transforming growth factor-beta activation in the lung: Focus on fibrosis and reactive oxygen species. Antioxid. Redox Signal. 2008;10:333–342. doi: 10.1089/ars.2007.1914.
    1. Dancea H.C., Shareef M.M., Ahmed M.M. Role of radiation-induced TGF-beta signaling in cancer therapy. Mol. Cell. Pharmacol. 2009;1:44–56. doi: 10.4255/mcpharmacol.09.06.
    1. Neuzillet C., Tijeras-Raballand A., Cohen R., Cros J., Faivre S., Raymond E., de Gramont A. Targeting the TGFbeta pathway for cancer therapy. Pharmacol. Ther. 2015;147:22–31. doi: 10.1016/j.pharmthera.2014.11.001.
    1. Akhurst R.J., Hata A. Targeting the tgfbeta signalling pathway in disease. Nat. Rev. Drug Discov. 2012;11:790–811. doi: 10.1038/nrd3810.
    1. Mu Y., Gudey S.K., Landstrom M. Non-smad signaling pathways. Cell Tissue Res. 2012;347:11–20. doi: 10.1007/s00441-011-1201-y.
    1. Zhang D., Chen X., Wang Q., Wu S., Zheng Y., Liu X. Role of the MAPKs/TGF-beta1/TRAF6 signaling pathway in postoperative atrial fibrillation. PLoS ONE. 2017;12:e0173759.
    1. Ji Y.X., Zhang P., Zhang X.J., Zhao Y.C., Deng K.Q., Jiang X., Wang P.X., Huang Z., Li H. The ubiquitin e3 ligase TRAF6 exacerbates pathological cardiac hypertrophy via tak1-dependent signalling. Nat. Commun. 2016;7:11267. doi: 10.1038/ncomms11267.
    1. Zhang D., Liu X., Chen X., Gu J., Li F., Zhang W., Zheng Y. Role of the MAPKs/TGF-beta1/TRAF6 signaling pathway in atrial fibrosis of patients with chronic atrial fibrillation and rheumatic mitral valve disease. Cardiology. 2014;129:216–223. doi: 10.1159/000366096.
    1. Divakaran V.G., Evans S., Topkara V.K., Diwan A., Burchfield J., Gao F., Dong J., Tzeng H.P., Sivasubramanian N., Barger P.M., et al. Tumor necrosis factor receptor-associated factor 2 signaling provokes adverse cardiac remodeling in the adult mammalian heart. Circ. Heart Fail. 2013;6:535–543. doi: 10.1161/CIRCHEARTFAILURE.112.000080.
    1. Jiang X., Deng K.Q., Luo Y., Jiang D.S., Gao L., Zhang X.F., Zhang P., Zhao G.N., Zhu X., Li H. Tumor necrosis factor receptor-associated factor 3 is a positive regulator of pathological cardiac hypertrophy. Hypertension. 2015;66:356–367. doi: 10.1161/HYPERTENSIONAHA.115.05469.
    1. Huang Y., Wu D., Zhang X., Jiang M., Hu C., Lin J., Tang J., Wu L. Cardiac-specific TRAF2 overexpression enhances cardiac hypertrophy through activating AKT/GSK3BETA signaling. Gene. 2014;536:225–231. doi: 10.1016/j.gene.2013.12.052.
    1. Moon G., Kim J., Min Y., Wi S.M., Shim J.H., Chun E., Lee K.Y. Phosphoinositide-dependent kinase-1 inhibits TRAF6 ubiquitination by interrupting the formation of TAK1-TAB2 complex in TLR4 signaling. Cell. Signal. 2015;27:2524–2533. doi: 10.1016/j.cellsig.2015.09.018.
    1. Yamashita M., Fatyol K., Jin C., Wang X., Liu Z., Zhang Y.E. TRAF6 mediates smad-independent activation of jnk and p38 by TGF-beta. Mol. Cell. 2008;31:918–924. doi: 10.1016/j.molcel.2008.09.002.
    1. Wang S., Campbell J., Stenmark M.H., Zhao J., Stanton P., Matuszak M.M., Ten Haken R.K., Kong F.S. Plasma levels of il-8 and TGF-beta1 predict radiation-induced lung toxicity in non-small cell lung cancer: A validation study. Int. J. Radiat. Oncol. Biol. Phys. 2017;98:615–621. doi: 10.1016/j.ijrobp.2017.03.011.
    1. Zhao L., Wang L., Ji W., Wang X., Zhu X., Hayman J.A., Kalemkerian G.P., Yang W., Brenner D., Lawrence T.S., et al. Elevation of plasma TGF-beta1 during radiation therapy predicts radiation-induced lung toxicity in patients with non-small-cell lung cancer: A combined analysis from beijing and michigan. Int. J. Radiat. Oncol. Biol. Phys. 2009;74:1385–1390. doi: 10.1016/j.ijrobp.2008.10.065.
    1. Johnston C.J., Piedboeuf B., Rubin P., Williams J.P., Baggs R., Finkelstein J.N. Early and persistent alterations in the expression of interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor alpha mrna levels in fibrosis-resistant and sensitive mice after thoracic irradiation. Radiat. Res. 1996;145:762–767. doi: 10.2307/3579368.
    1. Li X., Xu G., Qiao T., Yuan S., Zhuang X. Effects of CpG oligodeoxynucleotide 1826 on acute radiation-induced lung injury in mice. Biol. Res. 2016;49:8. doi: 10.1186/s40659-016-0068-5.
    1. Le Z., Niu X., Chen Y., Ou X., Zhao G., Liu Q., Tu W., Hu C., Kong L., Liu Y. Predictive single nucleotide polymorphism markers for acute oral mucositis in patients with nasopharyngeal carcinoma treated with radiotherapy. Oncotarget. 2017;8:63026–63037. doi: 10.18632/oncotarget.18450.
    1. Hill R.P., Zaidi A., Mahmood J., Jelveh S. Investigations into the role of inflammation in normal tissue response to irradiation. Radiother. Oncol. 2011;101:73–79. doi: 10.1016/j.radonc.2011.06.017.
    1. Ahmed M.M. Regulation of radiation-induced apoptosis by early growth response-1 gene in solid tumors. Curr. Cancer Drug Targets. 2004;4:43–52. doi: 10.2174/1568009043481704.
    1. Sathishkumar S., Dey S., Meigooni A.S., Regine W.F., Kudrimoti M.S., Ahmed M.M., Mohiuddin M. The impact of tnf-alpha induction on therapeutic efficacy following high dose spatially fractionated (grid) radiation. Technol. Cancer Res. Treat. 2002;1:141–147. doi: 10.1177/153303460200100207.
    1. Favaudon V., Caplier L., Monceau V., Pouzoulet F., Sayarath M., Fouillade C., Poupon M.F., Brito I., Hupe P., Bourhis J., et al. Ultrahigh dose-rate flash irradiation increases the differential response between normal and tumor tissue in mice. Sci. Transl. Med. 2014;6:245ra293. doi: 10.1126/scitranslmed.3008973.
    1. Weichhart T., Hengstschlager M., Linke M. Regulation of innate immune cell function by mTOR. Nat. Rev. Immunol. 2015;15:599–614. doi: 10.1038/nri3901.
    1. Linke M., Pham H.T., Katholnig K., Schnoller T., Miller A., Demel F., Schutz B., Rosner M., Kovacic B., Sukhbaatar N., et al. Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression. Nat. Immunol. 2017;18:293–302. doi: 10.1038/ni.3655.
    1. Wynn T.A., Vannella K.M. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016;44:450–462. doi: 10.1016/j.immuni.2016.02.015.
    1. Coward W.R., Saini G., Jenkins G. The pathogenesis of idiopathic pulmonary fibrosis. Ther. Adv. Respir. Dis. 2010;4:367–388. doi: 10.1177/1753465810379801.
    1. Sunilgowda S.N., Nagarajan D. Radiation-induced pulmonary epithelial-mesenchymal transition: A review of targeting molecular pathways and mediators. Curr. Drug Targets. 2018 doi: 10.2174/1389450119666180207092234.
    1. Li L.F., Kao K.C., Liu Y.Y., Lin C.W., Chen N.H., Lee C.S., Wang C.W., Yang C.T. Nintedanib reduces ventilation-augmented bleomycin-induced epithelial-mesenchymal transition and lung fibrosis through suppression of the src pathway. J. Cell. Mol. Med. 2017;21:2937–2949. doi: 10.1111/jcmm.13206.
    1. Sheppard D. Epithelial-mesenchymal interactions in fibrosis and repair. Transforming growth factor-beta activation by epithelial cells and fibroblasts. Ann. Am. Thorac. Soc. 2015;12(Suppl. S1):S21–S23. doi: 10.1513/AnnalsATS.201406-245MG.
    1. Horan G.S., Wood S., Ona V., Li D.J., Lukashev M.E., Weinreb P.H., Simon K.J., Hahm K., Allaire N.E., Rinaldi N.J., et al. Partial inhibition of integrin alpha(v)beta6 prevents pulmonary fibrosis without exacerbating inflammation. Am. J. Respir. Crit. Care Med. 2008;177:56–65. doi: 10.1164/rccm.200706-805OC.
    1. Linares J.F., Duran A., Yajima T., Pasparakis M., Moscat J., Diaz-Meco M.T. K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells. Mol. Cell. 2013;51:283–296. doi: 10.1016/j.molcel.2013.06.020.
    1. Lin G., Gai R., Chen Z., Wang Y., Liao S., Dong R., Zhu H., Gu Y., He Q., Yang B. The dual PI3K/mTOR inhibitor NVP-BEZ235 prevents epithelial-mesenchymal transition induced by hypoxia and TGF-beta1. Eur. J. Pharmacol. 2014;729:45–53. doi: 10.1016/j.ejphar.2014.02.011.
    1. Lamouille S., Derynck R. Emergence of the phosphoinositide 3-kinase-AKT-mammalian target of rapamycin axis in transforming growth factor-beta-induced epithelial-mesenchymal transition. Cells Tissues Organs. 2011;193:8–22. doi: 10.1159/000320172.
    1. Lamouille S., Connolly E., Smyth J.W., Akhurst R.J., Derynck R. Tgf-beta-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. J. Cell Sci. 2012;125:1259–1273. doi: 10.1242/jcs.095299.
    1. Cheng K., Hao M. Metformin inhibits TGF-beta1-induced epithelial-to-mesenchymal transition via PKM2 relative-mTOR/p70s6k signaling pathway in cervical carcinoma cells. Int. J. Mol. Sci. 2016;17:2000. doi: 10.3390/ijms17122000.
    1. Cheng K.Y., Hao M. Mammalian target of rapamycin (mTOR) regulates transforming growth factor-beta1 (TGF-beta1)-induced epithelial-mesenchymal transition via decreased pyruvate kinase m2 (pkm2) expression in cervical cancer cells. Med. Sci. Monit. 2017;23:2017–2028. doi: 10.12659/MSM.901542.
    1. Mikaelian I., Malek M., Gadet R., Viallet J., Garcia A., Girard-Gagnepain A., Hesling C., Gillet G., Gonzalo P., Rimokh R., et al. Genetic and pharmacologic inhibition of mTORC1 promotes emt by a TGF-beta-independent mechanism. Cancer Res. 2013;73:6621–6631. doi: 10.1158/0008-5472.CAN-13-0560.
    1. Mizushima N., Levine B., Cuervo A.M., Klionsky D.J. Autophagy fights disease through cellular self-digestion. Nature. 2008;451:1069–1075. doi: 10.1038/nature06639.
    1. Mehrpour M., Esclatine A., Beau I., Codogno P. Autophagy in health and disease. 1. Regulation and significance of autophagy: An overview. Am. J. Physiol. Cell Physiol. 2010;298:C776–C785. doi: 10.1152/ajpcell.00507.2009.
    1. Sridhar S., Botbol Y., Macian F., Cuervo A.M. Autophagy and disease: Always two sides to a problem. J. Pathol. 2012;226:255–273. doi: 10.1002/path.3025.
    1. Levine B., Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132:27–42. doi: 10.1016/j.cell.2007.12.018.
    1. Kim J., Kundu M., Viollet B., Guan K.L. AMPK and mTOR regulate autophagy through direct phosphorylation of ulk1. Nat. Cell Biol. 2011;13:132–141. doi: 10.1038/ncb2152.
    1. Kim J., Guan K.L. Regulation of the autophagy initiating kinase ULK1 by nutrients: Roles of mTORC1 and AMPK. Cell Cycle. 2011;10:1337–1338. doi: 10.4161/cc.10.9.15291.
    1. Hardie D.G. Ampk and autophagy get connected. EMBO J. 2011;30:634–635. doi: 10.1038/emboj.2011.12.
    1. Lee J.W., Park S., Takahashi Y., Wang H.G. The association of AMPK with ulk1 regulates autophagy. PLoS ONE. 2010;5:e15394. doi: 10.1371/journal.pone.0015394.
    1. Romero Y., Bueno M., Ramirez R., Alvarez D., Sembrat J.C., Goncharova E.A., Rojas M., Selman M., Mora A.L., Pardo A. MTORC1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in ipf fibroblasts. Aging Cell. 2016 doi: 10.1111/acel.12514.
    1. Paglin S., Yahalom J. Pathways that regulate autophagy and their role in mediating tumor response to treatment. Autophagy. 2006;2:291–293. doi: 10.4161/auto.2835.
    1. Paglin S., Lee N.Y., Nakar C., Fitzgerald M., Plotkin J., Deuel B., Hackett N., McMahill M., Sphicas E., Lampen N., et al. Rapamycin-sensitive pathway regulates mitochondrial membrane potential, autophagy, and survival in irradiated MCF-7 cells. Cancer Res. 2005;65:11061–11070. doi: 10.1158/0008-5472.CAN-05-1083.
    1. Chaachouay H., Ohneseit P., Toulany M., Kehlbach R., Multhoff G., Rodemann H.P. Autophagy contributes to resistance of tumor cells to ionizing radiation. Radiother. Oncol. 2011;99:287–292. doi: 10.1016/j.radonc.2011.06.002.
    1. Ondrej M., Cechakova L., Durisova K., Pejchal J., Tichy A. To live or let die: Unclear task of autophagy in the radiosensitization battle. Radiother. Oncol. 2016;119:265–275. doi: 10.1016/j.radonc.2016.02.028.
    1. Zhuang W., Li B., Long L., Chen L., Huang Q., Liang Z. Induction of autophagy promotes differentiation of glioma-initiating cells and their radiosensitivity. Int. J. Cancer. 2011;129:2720–2731. doi: 10.1002/ijc.25975.
    1. Martinez-Outschoorn U.E., Peiris-Pages M., Pestell R.G., Sotgia F., Lisanti M.P. Cancer metabolism: A therapeutic perspective. Nat. Rev. Clin. Oncol. 2017;14:113. doi: 10.1038/nrclinonc.2017.1.
    1. Judge J.L., Lacy S.H., Ku W.Y., Owens K.M., Hernady E., Thatcher T.H., Williams J.P., Phipps R.P., Sime P.J., Kottmann R.M. The lactate dehydrogenase inhibitor gossypol inhibits radiation-induced pulmonary fibrosis. Radiat. Res. 2017;188:35–43. doi: 10.1667/RR14620.1.
    1. Choi S.H., Hong Z.Y., Nam J.K., Lee H.J., Jang J., Yoo R.J., Lee Y.J., Lee C.Y., Kim K.H., Park S., et al. A hypoxia-induced vascular endothelial-to-mesenchymal transition in development of radiation-induced pulmonary fibrosis. Clin. Cancer Res. 2015;21:3716–3726. doi: 10.1158/1078-0432.CCR-14-3193.
    1. Westbury C.B., Pearson A., Nerurkar A., Reis-Filho J.S., Steele D., Peckitt C., Sharp G., Yarnold J.R. Hypoxia can be detected in irradiated normal human tissue: A study using the hypoxic marker pimonidazole hydrochloride. Br. J. Radiol. 2007;80:934–938. doi: 10.1259/bjr/25046649.
    1. Thind K., Chen A., Friesen-Waldner L., Ouriadov A., Scholl T.J., Fox M., Wong E., VanDyk J., Hope A., Santyr G. Detection of radiation-induced lung injury using hyperpolarized (13)c magnetic resonance spectroscopy and imaging. Magn. Reson. Med. 2013;70:601–609. doi: 10.1002/mrm.24525.
    1. Fox M.S., Ouriadov A., Thind K., Hegarty E., Wong E., Hope A., Santyr G.E. Detection of radiation induced lung injury in rats using dynamic hyperpolarized (129)Xe magnetic resonance spectroscopy. Med. Phys. 2014;41:072302. doi: 10.1118/1.4881523.
    1. Flockerzi E., Schanz S., Rube C.E. Even low doses of radiation lead to DNA damage accumulation in lung tissue according to the genetically-defined DNA repair capacity. Radiother. Oncol. 2014;111:212–218. doi: 10.1016/j.radonc.2014.03.011.
    1. Coppe J.P., Desprez P.Y., Krtolica A., Campisi J. The senescence-associated secretory phenotype: The dark side of tumor suppression. Annu. Rev. Pathol. 2010;5:99–118. doi: 10.1146/annurev-pathol-121808-102144.
    1. Hecker L., Logsdon N.J., Kurundkar D., Kurundkar A., Bernard K., Hock T., Meldrum E., Sanders Y.Y., Thannickal V.J. Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci. Transl. Med. 2014;6:231ra247. doi: 10.1126/scitranslmed.3008182.
    1. Kuwano K., Araya J., Hara H., Minagawa S., Takasaka N., Ito S., Kobayashi K., Nakayama K. Cellular senescence and autophagy in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) Respir. Investig. 2016;54:397–406. doi: 10.1016/j.resinv.2016.03.010.
    1. Yanai H., Shteinberg A., Porat Z., Budovsky A., Braiman A., Ziesche R., Fraifeld V.E. Cellular senescence-like features of lung fibroblasts derived from idiopathic pulmonary fibrosis patients. Aging (Albany NY) 2015;7:664–672. doi: 10.18632/aging.100807.
    1. Houssaini A., Breau M., Kebe K., Abid S., Marcos E., Lipskaia L., Rideau D., Parpaleix A., Huang J., Amsellem V., et al. Mtor pathway activation drives lung cell senescence and emphysema. JCI Insight. 2018;3:93203. doi: 10.1172/jci.insight.93203.
    1. Prasanna P.G., Stone H.B., Wong R.S., Capala J., Bernhard E.J., Vikram B., Coleman C.N. Normal tissue protection for improving radiotherapy: Where are the gaps? Transl. Cancer Res. 2012;1:35–48.
    1. Delanian S., Porcher R., Rudant J., Lefaix J.L. Kinetics of response to long-term treatment combining pentoxifylline and tocopherol in patients with superficial radiation-induced fibrosis. J. Clin. Oncol. 2005;23:8570–8579. doi: 10.1200/JCO.2005.02.4729.
    1. Haddad P., Kalaghchi B., Amouzegar-Hashemi F. Pentoxifylline and vitamin e combination for superficial radiation-induced fibrosis: A phase ii clinical trial. Radiother. Oncol. 2005;77:324–326. doi: 10.1016/j.radonc.2005.09.014.
    1. Magnusson M., Hoglund P., Johansson K., Jonsson C., Killander F., Malmstrom P., Weddig A., Kjellen E. Pentoxifylline and vitamin e treatment for prevention of radiation-induced side-effects in women with breast cancer: A phase two, double-blind, placebo-controlled randomised clinical trial (ptx-5) Eur. J. Cancer. 2009;45:2488–2495. doi: 10.1016/j.ejca.2009.05.015.
    1. Anscher M.S. The irreversibility of radiation-induced fibrosis: Fact or folklore? J. Clin. Oncol. 2005;23:8551–8552. doi: 10.1200/JCO.2005.03.6194.
    1. Park J.S., Park H.J., Park Y.S., Lee S.M., Yim J.J., Yoo C.G., Han S.K., Kim Y.W. Clinical significance of mTOR, ZEB1, ROCK1 expression in lung tissues of pulmonary fibrosis patients. BMC Pulm. Med. 2014;14:168. doi: 10.1186/1471-2466-14-168.
    1. Gui Y.S., Wang L., Tian X., Li X., Ma A., Zhou W., Zeng N., Zhang J., Cai B., Zhang H., et al. Mtor overactivation and compromised autophagy in the pathogenesis of pulmonary fibrosis. PLoS ONE. 2015;10:e0138625. doi: 10.1371/journal.pone.0138625.
    1. Wei X.X., Hsieh A.C., Kim W., Friedlander T., Lin A.M., Louttit M., Ryan C.J. A phase i study of abiraterone acetate combined with bez235, a dual PI3K/mTOR inhibitor, in metastatic castration resistant prostate cancer. Oncologist. 2017;22:e503–e543. doi: 10.1634/theoncologist.2016-0432.
    1. Nozawa M., Ohzeki T., Tamada S., Hongo F., Anai S., Fujimoto K., Miki T., Nakatani T., Fukasawa S., Uemura H. Differences in adverse event profiles between everolimus and temsirolimus and the risk factors for non-infectious pneumonitis in advanced renal cell carcinoma. Int. J. Clin. Oncol. 2015;20:790–795. doi: 10.1007/s10147-014-0764-5.
    1. Atkinson B.J., Cauley D.H., Ng C., Millikan R.E., Xiao L., Corn P., Jonasch E., Tannir N.M. Mammalian target of rapamycin (mTOR) inhibitor-associated non-infectious pneumonitis in patients with renal cell cancer: Predictors, management, and outcomes. BJU Int. 2014;113:376–382. doi: 10.1111/bju.12420.
    1. Albiges L., Chamming’s F., Duclos B., Stern M., Motzer R.J., Ravaud A., Camus P. Incidence and management of mTOR inhibitor-associated pneumonitis in patients with metastatic renal cell carcinoma. Ann. Oncol. 2012;23:1943–1953. doi: 10.1093/annonc/mds115.
    1. Penttila P., Donskov F., Rautiola J., Peltola K., Laukka M., Bono P. Everolimus-induced pneumonitis associates with favourable outcome in patients with metastatic renal cell carcinoma. Eur. J. Cancer. 2017;81:9–16. doi: 10.1016/j.ejca.2017.05.004.
    1. Popovich I.G., Anisimov V.N., Zabezhinski M.A., Semenchenko A.V., Tyndyk M.L., Yurova M.N., Blagosklonny M.V. Lifespan extension and cancer prevention in her-2/neu transgenic mice treated with low intermittent doses of rapamycin. Cancer Biol. Ther. 2014;15:586–592. doi: 10.4161/cbt.28164.
    1. Kondratov R.V., Kondratova A.A. Rapamycin in preventive (very low) doses. Aging (Albany NY) 2014;6:158–159. doi: 10.18632/aging.100645.
    1. Tao Z., Barker J., Shi S.D., Gehring M., Sun S. Steady-state kinetic and inhibition studies of the mammalian target of rapamycin (mTOR) kinase domain and mTOR complexes. Biochemistry. 2010;49:8488–8498. doi: 10.1021/bi100673c.
    1. Zhuge C.J., Chen S.J., Chin Y.E. Mtor and post-translational modifications rely on mitochondrion as the arsenal for cellular metabolism regulation. Sci. China Life Sci. 2015;58:810–812. doi: 10.1007/s11427-015-4909-1.
    1. Zoncu R., Efeyan A., Sabatini D.M. Mtor: From growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 2011;12:21–35. doi: 10.1038/nrm3025.
    1. Laplante M., Sabatini D.M. Regulation of mTORC1 and its impact on gene expression at a glance. J. Cell Sci. 2013;126:1713–1719. doi: 10.1242/jcs.125773.
    1. Mercer P.F., Woodcock H.V., Eley J.D., Plate M., Sulikowski M.G., Durrenberger P.F., Franklin L., Nanthakumar C.B., Man Y., Genovese F., et al. Exploration of a potent pi3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in ipf. Thorax. 2016;71:701–711. doi: 10.1136/thoraxjnl-2015-207429.
    1. Corboz M.R., Zhang J., LaSala D., DiPetrillo K., Li Z., Malinin V., Brower J., Kuehl P.J., Barrett T.E., Perkins W.R., et al. Therapeutic administration of inhaled ins1009, a treprostinil prodrug formulation, inhibits bleomycin-induced pulmonary fibrosis in rats. Pulm. Pharmacol. Ther. 2018 doi: 10.1016/j.pupt.2018.01.012.
    1. Tian X.L., Yao W., Guo Z.J., Gu L., Zhu Y.J. Low dose pirfenidone suppresses transforming growth factor beta-1 and tissue inhibitor of metalloproteinase-1, and protects rats from lung fibrosis induced by bleomycina. Chin. Med. Sci. J. 2006;21:145–151.
    1. Rasooli R., Rajaian H., Pardakhty A., Mandegary A. Preference of aerosolized pirfenidone to oral intake: An experimental model of pulmonary fibrosis by paraquat. J. Aerosol. Med. Pulm. Drug Deliv. 2018;31:25–32. doi: 10.1089/jamp.2016.1342.
    1. Varone F., Sgalla G., Iovene B., Bruni T., Richeldi L. Nintedanib for the treatment of idiopathic pulmonary fibrosis. Expert Opin. Pharmacother. 2018;19:167–175. doi: 10.1080/14656566.2018.1425681.
    1. Miura Y., Saito T., Tanaka T., Takoi H., Yatagai Y., Inomata M., Nei T., Saito Y., Gemma A., Azuma A. Reduced incidence of lung cancer in patients with idiopathic pulmonary fibrosis treated with pirfenidone. Respir. Investig. 2018;56:72–79. doi: 10.1016/j.resinv.2017.09.007.
    1. Fala L. Ofev (nintedanib): First tyrosine kinase inhibitor approved for the treatment of patients with idiopathic pulmonary fibrosis. Am. Health Drug Benefits. 2015;8:101–104.
    1. Kurita Y., Araya J., Minagawa S., Hara H., Ichikawa A., Saito N., Kadota T., Tsubouchi K., Sato N., Yoshida M., et al. Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy. Respir. Res. 2017;18:114. doi: 10.1186/s12931-017-0600-3.
    1. Liu Y., Lu F., Kang L., Wang Z., Wang Y. Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating nrf2/bach1 equilibrium. BMC Pulm. Med. 2017;17:63. doi: 10.1186/s12890-017-0405-7.
    1. Kurimoto R., Ebata T., Iwasawa S., Ishiwata T., Tada Y., Tatsumi K., Takiguchi Y. Pirfenidone may revert the epithelial-to-mesenchymal transition in human lung adenocarcinoma. Oncol. Lett. 2017;14:944–950. doi: 10.3892/ol.2017.6188.
    1. Li Z., Liu X., Wang B., Nie Y., Wen J., Wang Q., Gu C. Pirfenidone suppresses mapk signalling pathway to reverse epithelial-mesenchymal transition and renal fibrosis. Nephrology (Carlton) 2017;22:589–597. doi: 10.1111/nep.12831.
    1. Wollin L., Wex E., Pautsch A., Schnapp G., Hostettler K.E., Stowasser S., Kolb M. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur. Respir. J. 2015;45:1434–1445. doi: 10.1183/09031936.00174914.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj