Fatty Acid Metabolism, Bone Marrow Adipocytes, and AML

Yoko Tabe, Marina Konopleva, Michael Andreeff, Yoko Tabe, Marina Konopleva, Michael Andreeff

Abstract

Acute myeloid leukemia (AML) cells modulate their metabolic state continuously as a result of bone marrow (BM) microenvironment stimuli and/or nutrient availability. Adipocytes are prevalent in the BM stroma and increase in number with age. AML in elderly patients induces remodeling and lipolysis of BM adipocytes, which may promote AML cell survival through metabolic activation of fatty acid oxidation (FAO). FAO reactions generate acetyl-CoA from fatty acids under aerobic conditions and, under certain conditions, it can cause uncoupling of mitochondrial oxidative phosphorylation. Recent experimental evidence indicates that FAO is associated with quiescence and drug-resistance in leukemia stem cells. In this review, we highlight recent progress in our understanding of fatty acid metabolism in AML cells in the adipocyte-rich BM microenvironment, and discuss the therapeutic potential of combinatorial regimens with various FAO inhibitors, which target metabolic vulnerabilities of BM-resident, chemoresistant leukemia cells.

Keywords: adipocyte; bone marrow microenvironment; fatty acid metabolism; fatty acid oxidation; therapy resistance.

Copyright © 2020 Tabe, Konopleva and Andreeff.

Figures

Figure 1
Figure 1
The bone marrow microenvironment reprograms energy metabolism in AML. AML cells utilize multiple metabolic pathways for energy production, glycolysis, oxidative phosphorylation (OXPHOS), and if fatty acid is available, also undergo fatty acid oxidation (FAO). In the oxidative stressed bone marrow (BM) microenvironment, AML cells are supplied free fatty acids by abundant BM adipocytes, and utilize for FAO. FAO involves a series of reactions to generate acetyl-CoA from fatty acid under aerobic conditions. Acetyl-CoA enters the TCA cycle.
Figure 2
Figure 2
Interactions with adipocytes promotes fatty acid metabolism in AML. BM adipocytes prevent cell death of AML via FAO stimulation, with activation of AMPK and HSP chaperone proteins and modulation of transcription factors in vitro. (A) Fatty acids are obtained from the extracellular microenvironment through lipolysis of stored triglycerides in adipocytes. (B) BM adipocytes induce upregulation of PPARγ, CD36, and FABP4 gene transcription, which stimulates fatty acid endocytosis. The networks of transcriptional regulation and fatty acid metabolism support AML cells in a quiescent state associated with activation of AMPK, p38 with autophagy induction, upregulation of HSP anti-apoptotic chaperone proteins and chemoresistance. (C) In mitochondria, fatty acids are consumed for FAO, resulting in decrease of mitochondrial ROS formation and intracellular oxidative stress. FAO inhibition induces the integrated stress response, which stimulates transcriptional activation of ATF4 and facilitates apoptosis induction by chemotherapeutic drug. FABP4, fatty acid binding protein 4; AMPK, AMP-activated protein kinase; p38, p38 mitogen-activated protein kinase; ADIPOR1, adiponectin receptor 1; ATF4, activating transcription factor 4.

References

    1. Jones RG, Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. (2009) 23:537–48. 10.1101/gad.1756509
    1. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. (2009) 324:1029–33. 10.1126/science.1160809
    1. Pietrocola F, Galluzzi L, Bravo-San Pedro JM, Madeo F, Kroemer G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. (2015) 21:805–21. 10.1016/j.cmet.2015.05.014
    1. Hassan M, Abedi-Valugerdi M. Hematologic malignancies in elderly patients. Haematologica. (2014) 99:1124–7. 10.3324/haematol.2014.107557
    1. Justesen J, Stenderup K, Ebbesen EN, Mosekilde L, Steiniche T, Kassem M. Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis. Biogerontology. (2001) 2:165–71. 10.1023/A:1011513223894
    1. Behan JW, Yun JP, Proektor MP, Ehsanipour EA, Arutyunyan A, Moses AS, et al. . Adipocytes impair leukemia treatment in mice. Cancer Res. (2009) 69:7867–74. 10.1158/0008-5472.CAN-09-0800
    1. Röhrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer. (2016) 16:732–49. 10.1038/nrc.2016.89
    1. Beloribi-Djefaflia S, Vasseur S, Guillaumond F. Lipid metabolic reprogramming in cancer cells. Oncogenesis. (2016) 5:e189. 10.1038/oncsis.2015.49
    1. Samudio I, Harmancey R, Fiegl M, Kantarjian H, Konopleva M, Korchin B, et al. . Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest. (2010) 120:142–56. 10.1172/JCI38942
    1. Fiegl M, Samudio I, Clise-Dwyer K, Burks JK, Mnjoyan Z, Andreeff M. CXCR4 expression and biologic activity in acute myeloid leukemia are dependent on oxygen partial pressure. Blood. (2009) 113:1504–12. 10.1182/blood-2008-06-161539
    1. Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S, et al. . A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. (2010) 141:69–80. 10.1016/j.cell.2010.02.027
    1. Hirsch HA, Iliopoulos D, Joshi A, Zhang Y, Jaeger SA, Bulyk M, et al. . A transcriptional signature and common gene networks link cancer with lipid metabolism and diverse human diseases. Cancer Cell. (2010) 17:348–61. 10.1016/j.ccr.2010.01.022
    1. Ye H, Adane B, Khan N, Sullivan T, Minhajuddin M, Gasparetto M, et al. . Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. Cell Stem Cell. (2016) 19:23–37. 10.1016/j.stem.2016.06.001
    1. Lobo NA, Shimono Y, Qian D, Clarke MF. The biology of cancer stem cells. Annu Rev Cell Dev Biol. (2007) 23:675–99. 10.1146/annurev.cellbio.22.010305.104154
    1. Boroughs LK, DeBerardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol. (2015) 17:351–9. 10.1038/ncb3124
    1. Jeon SM, Chandel NS, Hay N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature. (2012) 485:661–5. 10.1038/nature11066
    1. Kruiswijk F, Labuschagne CF, Vousden KH. p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol. (2015) 16:393–405. 10.1038/nrm4007
    1. Carracedo A, Cantley LC, Pandolfi PP. Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer. (2013) 13:227–32. 10.1038/nrc3483
    1. Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, et al. . Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. (2011) 17:1498–503. 10.1038/nm.2492
    1. Itoh T, Fairall L, Amin K, Inaba Y, Szanto A, Balint BL, et al. . Structural basis for the activation of PPARgamma by oxidized fatty acids. Nat Struct Mol Biol. (2008) 15:924–31. 10.1038/nsmb.1474
    1. Carmen GY, Victor SM. Signalling mechanisms regulating lipolysis. Cell Signal. (2006) 18:401–8. 10.1016/j.cellsig.2005.08.009
    1. Sengenes C, Bouloumie A, Hauner H, Berlan M, Busse R, Lafontan M, et al. . Involvement of a cGMP-dependent pathway in the natriuretic peptide-mediated hormone-sensitive lipase phosphorylation in human adipocytes. J Biol Chem. (2003) 278:48617–26. 10.1074/jbc.M303713200
    1. Brasaemle DL, Subramanian V, Garcia A, Marcinkiewicz A, Rothenberg A. Perilipin A and the control of triacylglycerol metabolism. Mol Cell Biochem. (2009) 326:15–21. 10.1007/s11010-008-9998-8
    1. Shafat MS, Oellerich T, Mohr S, Robinson SD, Edwards DR, Marlein CR, et al. . Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment. Blood. (2017) 129:1320–32. 10.1182/blood-2016-08-734798
    1. Tabe Y, Yamamoto S, Saitoh K, Sekihara K, Monma N, Ikeo K, et al. . Bone marrow adipocytes facilitate fatty acid oxidation activating AMPK and a transcriptional network supporting survival of acute monocytic leukemia cells. Cancer Res. (2017) 77:1453–64. 10.1158/0008-5472.CAN-16-1645
    1. Herroon MK, Rajagurubandara E, Hardaway AL, Powell K, Turchick A, Feldmann D, et al. . Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms. Oncotarget. (2013) 4:2108–23. 10.18632/oncotarget.1482
    1. Velez J, Hail N, Jr, Konopleva M, Zeng Z, Kojima K, Samudio I, et al. . Mitochondrial uncoupling and the reprograming of intermediary metabolism in leukemia cells. Front Oncol. (2013) 3:67. 10.3389/fonc.2013.00067
    1. Wilkins HM, Marquardt K, Lash LH, Linseman DA. Bcl-2 is a novel interacting partner for the 2-oxoglutarate carrier and a key regulator of mitochondrial glutathione. Free Radic Biol Med. (2012) 52:410–9. 10.1016/j.freeradbiomed.2011.10.495
    1. Low IC, Chen ZX, Pervaiz S. Bcl-2 modulates resveratrol-induced ROS production by regulating mitochondrial respiration in tumor cells. Antioxid Redox Signal. (2010) 13:807–19. 10.1089/ars.2009.3050
    1. Armstrong JS, Steinauer KK, French J, Killoran PL, Walleczek J, Kochanski J, et al. . Bcl-2 inhibits apoptosis induced by mitochondrial uncoupling but does not prevent mitochondrial transmembrane depolarization. Exp Cell Res. (2001) 262:170–9. 10.1006/excr.2000.5091
    1. Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, et al. . BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. (2013) 12:329–41. 10.1016/j.stem.2012.12.013
    1. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, et al. . Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. (2002) 8:1288–95. 10.1038/nm788
    1. Alers S, Löffler AS, Wesselborg S, Stork B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol. (2012) 32:2–11. 10.1128/MCB.06159-11
    1. Cawthorn WP, Scheller EL, Learman BS, Parlee SD, Simon BR, Mori H, et al. . Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction. Cell Metab. (2014) 20:368–75. 10.1016/j.cmet.2014.06.003
    1. Medina EA, Oberheu K, Polusani SR, Ortega V, Velagaleti GV, Oyajobi BO. PKA/AMPK signaling in relation to adiponectin's antiproliferative effect on multiple myeloma cells. Leukemia. (2014) 28:2080–9. 10.1038/leu.2014.112
    1. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, et al. . AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. (2008) 30:214–26. 10.1016/j.molcel.2008.03.003
    1. Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, et al. . Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature. (2010) 464:1313–9. 10.1038/nature08991
    1. Stine ZE, Walton ZE, Altman BJ, Hsieh AL, Dang CV. MYC, metabolism, and cancer. Cancer Discov. (2015) 5:1024–39. 10.1158/-15-0507
    1. Sancho P, Barneda D, Heeschen C. Hallmarks of cancer stem cell metabolism. Br J Cancer. (2016) 114:1305–12. 10.1038/bjc.2016.152
    1. Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO, et al. . Normal and neoplastic non-stem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci USA. (2011) 108:7950–5. 10.1073/pnas.1102454108
    1. Coort SL, Willems J, Coumans WA, van der Vusse GJ, Bonen A, Glatz JF, et al. . Sulfo-N-succinimidyl esters of long chain fatty acids specifically inhibit fatty acid translocase (FAT/CD36)-mediated cellular fatty acid uptake. Mol Cell Biochem. (2002) 239:213–9. 10.1023/A:1020539932353
    1. Greenwalt DE, Scheck SH, Rhinehart-Jones T. Heart CD36 expression is increased in murine models of diabetes and in mice fed a high fat diet. J Clin Invest. (1995) 96:1382–8. 10.1172/JCI118173
    1. Pascual G, Avgustinova A, Mejetta S, Martin M, Castellanos A, Attolini CS, et al. . Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature. (2017) 541:41–5. 10.1038/nature20791
    1. Tokuda Y, Satoh Y, Fujiyama C, Toda S, Sugihara H, Masaki Z. Prostate cancer cell growth is modulated by adipocyte-cancer cell interaction. BJU Int. (2003) 91:716–20. 10.1046/j.1464-410X.2003.04218.x
    1. Dirat B, Bochet L, Dabek M, Daviaud D, Dauvillier S, Majed B, et al. . Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. (2011) 71:2455–65. 10.1158/0008-5472.CAN-10-3323
    1. Jones CL, Stevens BM, D'Alessandro A, Reisz JA, Culp-Hill R, Nemkov T, et al. . Inhibition of amino acid metabolism selectively targets human leukemia stem cells. Cancer Cell. (2019) 35:333–5. 10.1016/j.ccell.2019.01.013
    1. Tabe Y, Saitoh K, Yang H, Sekihara K, Yamatani K, Ruvolo V, et al. . Inhibition of FAO in AML co-cultured with BM adipocytes: mechanisms of survival and chemosensitization to cytarabine. Sci Rep. (2018) 8:16837. 10.1038/s41598-018-35198-6
    1. Qu Q, Zeng F, Liu X, Wang QJ, Deng F. Fatty acid oxidation and carnitine palmitoyltransferase I: emerging therapeutic targets in cancer. Cell Death Dis. (2016) 7:e2226. 10.1038/cddis.2016.132
    1. Pike LS, Smift AL, Croteau NJ, Ferrick DA, Wu M. Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. Biochim Biophys Acta. (2011) 1807:726–34. 10.1016/j.bbabio.2010.10.022
    1. Ricciardi MR, Mirabilii S, Allegretti M, Licchetta R, Calarco A, Torrisi MR, et al. . Targeting the leukemia cell metabolism by the CPT1a inhibition: functional preclinical effects in leukemias. Blood. (2015) 126:1925–9. 10.1182/blood-2014-12-617498
    1. Schreurs M, Kuipers F, van der Leij FR. Regulatory enzymes of mitochondrial beta-oxidation as targets for treatment of the metabolic syndrome. Obes Rev. (2010) 11:380–8. 10.1111/j.1467-789X.2009.00642.x
    1. Yao CH, Liu GY, Wang R, Moon SH, Gross RW, Patti GJ. Identifying off-target effects of etomoxir reveals that carnitine palmitoyltransferase I is essential for cancer cell proliferation independent of beta-oxidation. PLoS Biol. (2018) 16:e2003782. 10.1371/journal.pbio.2003782
    1. Wang T, Fahrmann JF, Lee H, Li YJ, Tripathi SC, Yue C, et al. JAK/STAT3-regulated fatty acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab. (2018) 27:1357 10.1016/j.cmet.2018.04.018
    1. Kim WT, Yun SJ, Yan C, Jeong P, Kim YH, Lee IS, et al. . Metabolic pathway signatures associated with urinary metabolite biomarkers differentiate bladder cancer patients from healthy controls. Yonsei Med J. (2016) 57:865–71. 10.3349/ymj.2016.57.4.865
    1. Zaugg K, Yao Y, Reilly PT, Kannan K, Kiarash R, Mason J, et al. . Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. (2011) 25:1041–51. 10.1101/gad.1987211
    1. Holubarsch CJ, Rohrbach M, Karrasch M, Boehm E, Polonski L, Ponikowski P, et al. . A double-blind randomized multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: the ERGO (etomoxir for the recovery of glucose oxidation) study. Clin Sci. (2007) 113:205–12. 10.1042/CS20060307
    1. Yin X, Dwyer J, Langley SR, Mayr U, Xing Q, Drozdov I, et al. . Effects of perhexiline-induced fuel switch on the cardiac proteome and metabolome. J Mol Cell Cardiol. (2013) 55:27–30. 10.1016/j.yjmcc.2012.12.014
    1. Lee EA, Angka L, Rota SG, Hanlon T, Mitchell A, Hurren R, et al. . Targeting mitochondria with avocatin B induces selective leukemia cell death. Cancer Res. (2015) 75:2478–88. 10.1158/0008-5472.CAN-14-2676
    1. Tcheng M, Samudio I, Lee EA, Minden MD, Spagnuolo PA. The mitochondria target drug avocatin B synergizes with induction chemotherapeutics to induce leukemia cell death. Leuk Lymphoma. (2017) 58:986–8. 10.1080/10428194.2016.1218005
    1. Zhang Y, Li F, Patterson AD, Wang Y, Krausz KW, Neale G, et al. . Abcb11 deficiency induces cholestasis coupled to impaired β-fatty acid oxidation in mice. J Biol Chem. (2012) 287:24784–94. 10.1074/jbc.M111.329318
    1. Farge T, Saland E, de Toni F, Aroua N, Hosseini M, Perry R, et al. . Chemotherapy resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism. Cancer Discov. (2017) 7:716–35. 10.1158/-16-0441
    1. Hermanova I, Arruabarrena-Aristorena A, Valis K, Nuskova H, Alberich-Jorda M, Fiser K, et al. . Pharmacological inhibition of fatty-acid oxidation synergistically enhances the effect of l-asparaginase in childhood ALL cells. Leukemia. (2016) 30:209–18. 10.1038/leu.2015.213
    1. Shinohara H, Kumazaki M, Minami Y, Ito Y, Sugito N, Kuranaga Y, et al. . Perturbation of energy metabolism by fatty-acid derivative AIC-47 and imatinib in BCR-ABL-harboring leukemic cells. Cancer Lett. (2016) 371:1–11. 10.1016/j.canlet.2015.11.020
    1. Shinohara H, Sugito N, Kuranaga Y, Heishima K, Minami Y, Naoe T, et al. . Potent antiproliferative effect of fatty-acid derivative AIC-47 on leukemic mice harboring BCR-ABL mutation. Cancer Sci. (2019) 110:751–60. 10.1111/cas.13913
    1. Tung S, Shi Y, Wong K, Zhu F, Gorczynski R, Laister RC, et al. . PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia. Blood. (2013) 122:969–80. 10.1182/blood-2013-03-489468

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