The role of PPARγ in prostate cancer development and progression

Andrew Hartley, Imran Ahmad, Andrew Hartley, Imran Ahmad

Abstract

Advanced and metastatic prostate cancer is often incurable, but its dependency on certain molecular alterations may provide the basis for targeted therapies. A growing body of research has demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) is amplified as prostate cancer progresses. PPARγ has been shown to support prostate cancer growth through its roles in fatty acid synthesis, mitochondrial biogenesis, and co-operating with androgen receptor signalling. Interestingly, splice variants of PPARγ may have differing and contrasting roles. PPARγ itself is a highly druggable target, with agonists having been used for the past two decades in treating diabetes. However, side effects associated with these compounds have currently limited clinical use of these drugs in prostate cancer. Further understanding of PPARγ and novel techniques to target it, may provide therapies for advanced prostate cancer.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1. Comparison of PPARγ splice variants.
Fig. 1. Comparison of PPARγ splice variants.
Various PPARγ splice variants can be produced by alternative splicing events including exon skipping and readthrough. These variants each have unique structures and tissues specificity. The most well studied variants PPARγ1 and PPARγ1 however are of the most interest in prostate cancer currently.
Fig. 2. PPARγ signalling that positively regulate…
Fig. 2. PPARγ signalling that positively regulate prostate cancer growth.
PPARγ peroxisome proliferator-activated receptor gamma, FASN fatty acid synthase, ACYL ATP citrate lyase, AR androgen receptor, AKT3 AKT serine/threonine kinase 3, CRM1 chromosome region maintenance 1, PCG1α PPARG coactivator 1 alpha.
Fig. 3. PPARγ alterations in PC (CBioPortal).
Fig. 3. PPARγ alterations in PC (CBioPortal).
PPARγ alterations visualised using CBioPortal [42, 43]. Prostate adenocarcinoma TCGA (51) was used as the primary prostate cancer cohort [40]. Metastatic prostate adenocarcinoma (SU2C/PCF) was used as the metastatic prostate cancer cohort [41]. For mRNA dysregulation, a z-score of >1.2 was used as a threshold relative to all samples.

References

    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29. doi: 10.3322/caac.21254.
    1. Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J Clin. 1972;22:232–40. doi: 10.3322/canjclin.22.4.232.
    1. Maitland NJ. Resistance to antiandrogens in prostate cancer: is it inevitable, intrinsic or induced? Cancers. 2021;13:327.
    1. Wang X, Sun B, Wei L, Jian X, Shan K, He Q, et al. Cholesterol and saturated fatty acids synergistically promote the malignant progression of prostate cancer. Neoplasia. 2022;24:86–97. doi: 10.1016/j.neo.2021.11.004.
    1. Wu X, Daniels G, Lee P, Monaco ME. Lipid metabolism in prostate cancer. Am J Clin Exp Urol. 2014;2:111–20.
    1. Rosen ED, Spiegelman BM. PPARgamma: a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem. 2001;276:37731–4. doi: 10.1074/jbc.R100034200.
    1. Ijpenberg A, Jeannin E, Wahli W, Desvergne B. Polarity and specific sequence requirements of peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor heterodimer binding to DNA: a functional analysis of the malic enzyme gene PPAR response element. J Biol Chem. 1997;272:20108–17. doi: 10.1074/jbc.272.32.20108.
    1. Tzeng J, Byun J, Park JY, Yamamoto T, Schesing K, Tian B, et al. An ideal PPAR response element bound to and activated by PPARα. PLoS ONE. 2015;10:e0134996. doi: 10.1371/journal.pone.0134996.
    1. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, et al. PPARγ signaling and metabolism: the good, the bad and the future. Nat Med. 2013;19:557–66. doi: 10.1038/nm.3159.
    1. Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM. Transcriptional regulation of adipogenesis. Genes Dev. 2000;14:1293–307. doi: 10.1101/gad.14.11.1293.
    1. Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, et al. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell. 1999;4:611–7. doi: 10.1016/S1097-2765(00)80211-7.
    1. Wu Z, Rosen ED, Brun R, Hauser S, Adelmant G, Troy AE, et al. Cross-regulation of C/EBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol Cell. 1999;3:151–8. doi: 10.1016/S1097-2765(00)80306-8.
    1. Rosen ED, Hsu CH, Wang X, Sakai S, Freeman MW, Gonzalez FJ, et al. C/EBPalpha induces adipogenesis through PPARgamma: a unified pathway. Genes Dev. 2002;16:22–6. doi: 10.1101/gad.948702.
    1. Trombetta A, Maggiora M, Martinasso G, Cotogni P, Canuto RA, Muzio G. Arachidonic and docosahexaenoic acids reduce the growth of A549 human lung-tumor cells increasing lipid peroxidation and PPARs. Chem Biol Interact. 2007;165:239–50. doi: 10.1016/j.cbi.2006.12.014.
    1. Heim M, Johnson J, Boess F, Bendik I, Weber P, Hunziker W, et al. Phytanic acid, a natural peroxisome proliferator-activated receptor (PPAR) agonist, regulates glucose metabolism in rat primary hepatocytes. FASEB J. 2002;16:718–20. doi: 10.1096/fj.01-0816fje.
    1. Hauner H. The mode of action of thiazolidinediones. Diabetes Metab Res Rev. 2002;18:S10–5. doi: 10.1002/dmrr.249.
    1. Kletzien RF, Clarke SD, Ulrich RG. Enhancement of adipocyte differentiation by an insulin-sensitizing agent. Mol Pharmacol. 1992;41:393–8.
    1. Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 1994;8:1224–34. doi: 10.1101/gad.8.10.1224.
    1. Werman A, Hollenberg A, Solanes G, Bjorbaek C, Vidal-Puig AJ, Flier JS. Ligand-independent activation domain in the N terminus of peroxisome proliferator-activated receptor gamma (PPARgamma). Differential activity of PPARgamma1 and -2 isoforms and influence of insulin. J Biol Chem. 1997;272:20230–5. doi: 10.1074/jbc.272.32.20230.
    1. Fajas L, Auboeuf D, Raspe E, Schoonjans K, Lefebvre AM, Saladin R, et al. The organization, promoter analysis, and expression of the human PPARgamma gene. J Biol Chem. 1997;272:18779–89. doi: 10.1074/jbc.272.30.18779.
    1. Tran L, Bobe G, Arani G, Zhang Y, Zhang Z, Shannon J, et al. Diet and PPARG2 Pro12Ala polymorphism interactions in relation to cancer risk: a systematic review. Nutrients. 2021;13:261.
    1. Li F, Lu T, Liu D, Zhang C, Zhang Y, Dong F. Upregulated PPARG2 facilitates interaction with demethylated AKAP12 gene promoter and suppresses proliferation in prostate cancer. Cell Death Dis. 2021;12:528. doi: 10.1038/s41419-021-03820-7.
    1. Aprile M, Cataldi S, Ambrosio MR, D’Esposito V, Lim K, Dietrich A, et al. PPARγΔ5, a naturally occurring dominant-negative splice isoform, impairs PPARγ function and adipocyte differentiation. Cell Rep. 2018;25:1577.e6–92.e6. doi: 10.1016/j.celrep.2018.10.035.
    1. Sabatino L, Casamassimi A, Peluso G, Barone MV, Capaccio D, Migliore C, et al. A novel peroxisome proliferator-activated receptor gamma isoform with dominant negative activity generated by alternative splicing. J Biol Chem. 2005;280:26517–25. doi: 10.1074/jbc.M502716200.
    1. Mukha A, Kalkhoven E, van Mil SWC. Splice variants of metabolic nuclear receptors: Relevance for metabolic disease and therapeutic targeting. Biochimica et Biophysica Acta Mol Basis Dis. 2021;1867:166183. doi: 10.1016/j.bbadis.2021.166183.
    1. Ahmad I, Mui E, Galbraith L, Patel R, Tan EH, Salji M, et al. Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer. Proc Natl Acad Sci USA. 2016;113:8290–5. doi: 10.1073/pnas.1601571113.
    1. Galbraith LCA, Mui E, Nixon C, Hedley A, Strachan D, MacKay G, et al. PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer. Oncogene. 2021;40:2355–66. doi: 10.1038/s41388-021-01707-7.
    1. Miglio G, Rosa AC, Rattazzi L, Collino M, Lombardi G, Fantozzi R. PPARgamma stimulation promotes mitochondrial biogenesis and prevents glucose deprivation-induced neuronal cell loss. Neurochem Int. 2009;55:496–504. doi: 10.1016/j.neuint.2009.05.001.
    1. Rong JX, Klein JL, Qiu Y, Xie M, Johnson JH, Waters KM, et al. Rosiglitazone induces mitochondrial biogenesis in differentiated murine 3T3-L1 and C3H/10T1/2 adipocytes. PPAR Res. 2011;2011:179454. doi: 10.1155/2011/179454.
    1. Liu C, Tate T, Batourina E, Truschel ST, Potter S, Adam M, et al. Pparg promotes differentiation and regulates mitochondrial gene expression in bladder epithelial cells. Nat Commun. 2019;10:4589. doi: 10.1038/s41467-019-12332-0.
    1. Strand DW, Jiang M, Murphy TA, Yi Y, Konvinse KC, Franco OE, et al. PPARγ isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation. Cell Death Dis. 2012;3:e361. doi: 10.1038/cddis.2012.99.
    1. Mueller E, Drori S, Aiyer A, Yie J, Sarraf P, Chen H, et al. Genetic analysis of adipogenesis through peroxisome proliferator-activated receptor gamma isoforms. J Biol Chem. 2002;277:41925–30. doi: 10.1074/jbc.M206950200.
    1. Aprile M, Ambrosio MR, D’Esposito V, Beguinot F, Formisano P, Costa V, et al. PPARG in human adipogenesis: differential contribution of canonical transcripts and dominant negative isoforms. PPAR Res. 2014;2014:537865. doi: 10.1155/2014/537865.
    1. Tew BY, Hong TB, Otto-Duessel M, Elix C, Castro E, He M, et al. Vitamin K epoxide reductase regulation of androgen receptor activity. Oncotarget. 2017;8:13818–31. doi: 10.18632/oncotarget.14639.
    1. Patel S, Singh R, Preuss CV, Patel N. Warfarin. Treasure Island (FL): StatPearls Publishing LLC.; 2022.
    1. Olokpa E, Bolden A, Stewart LV. The androgen receptor regulates PPARγ expression and activity in human prostate cancer cells. J Cell Physiol. 2016;231:2664–72. doi: 10.1002/jcp.25368.
    1. Moss PE, Lyles BE, Stewart LV. The PPARγ ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells. Exp Cell Res. 2010;316:3478–88. doi: 10.1016/j.yexcr.2010.09.015.
    1. Galbraith L, Leung HY, Ahmad I. Lipid pathway deregulation in advanced prostate cancer. Pharmacol Res. 2018;131:177–84. doi: 10.1016/j.phrs.2018.02.022.
    1. Durbin RJ. Thiazolidinedione therapy in the prevention/delay of type 2 diabetes in patients with impaired glucose tolerance and insulin resistance. Diabetes Obes Metab. 2004;6:280–5. doi: 10.1111/j.1462-8902.2004.0348.x.
    1. Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes. 1998;47:507–14. doi: 10.2337/diabetes.47.4.507.
    1. Govindarajan R, Ratnasinghe L, Simmons DL, Siegel ER, Midathada MV, Kim L, et al. Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. J Clin Oncol. 2007;25:1476–81. doi: 10.1200/JCO.2006.07.2777.
    1. Nath M, Nath S, Choudhury Y. The impact of thiazolidinediones on the risk for prostate cancer in patients with type 2 diabetes mellitus: a review and meta-analysis. Meta Gene. 2021;27:100840. doi: 10.1016/j.mgene.2020.100840.
    1. He XX, Tu SM, Lee MH, Yeung SJ. Thiazolidinediones and metformin associated with improved survival of diabetic prostate cancer patients. Ann Oncol. 2011;22:2640–5. doi: 10.1093/annonc/mdr020.
    1. Kubota T, Koshizuka K, Williamson EA, Asou H, Said JW, Holden S, et al. Ligand for peroxisome proliferator-activated receptor gamma (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res. 1998;58:3344–52.
    1. Hisatake JI, Ikezoe T, Carey M, Holden S, Tomoyasu S, Koeffler HP. Down-regulation of prostate-specific antigen expression by ligands for peroxisome proliferator-activated receptor gamma in human prostate cancer. Cancer Res. 2000;60:5494–8.
    1. Wang YL, Frauwirth KA, Rangwala SM, Lazar MA, Thompson CB. Thiazolidinedione activation of peroxisome proliferator-activated receptor gamma can enhance mitochondrial potential and promote cell survival. J Biol Chem. 2002;277:31781–8. doi: 10.1074/jbc.M204279200.
    1. Akinyeke TO, Stewart LV. Troglitazone suppresses c-Myc levels in human prostate cancer cells via a PPARγ-independent mechanism. Cancer Biol Ther. 2011;11:1046–58. doi: 10.4161/cbt.11.12.15709.
    1. Bolden A, Bernard L, Jones D, Akinyeke T, Stewart LV. The PPAR gamma agonist troglitazone regulates Erk 1/2 phosphorylation via a PPARγ-independent, MEK-dependent pathway in human prostate cancer cells. PPAR Res. 2012;2012:929052. doi: 10.1155/2012/929052.
    1. Rogenhofer S, Ellinger J, Kahl P, Stoehr C, Hartmann A, Engehausen D, et al. Enhanced expression of peroxisome proliferate-activated receptor gamma (PPAR-γ) in advanced prostate cancer. Anticancer Res. 2012;32:3479–83.
    1. Segawa Y, Yoshimura R, Hase T, Nakatani T, Wada S, Kawahito Y, et al. Expression of peroxisome proliferator-activated receptor (PPAR) in human prostate cancer. Prostate. 2002;51:108–16. doi: 10.1002/pros.10058.
    1. The Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011–25.
    1. Abida W, Cyrta J, Heller G, Prandi D, Armenia J, Coleman I, et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci USA. 2019;116:11428–36. doi: 10.1073/pnas.1902651116.
    1. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4. doi: 10.1158/-12-0095.
    1. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1. doi: 10.1126/scisignal.2004088.
    1. Hasstedt SJ, Ren QF, Teng K, Elbein SC. Effect of the peroxisome proliferator-activated receptor-gamma 2 pro(12)ala variant on obesity, glucose homeostasis, and blood pressure in members of familial type 2 diabetic kindreds. J Clin Endocrinol Metab. 2001;86:536–41.
    1. Wang W, Shao Y, Tang S, Cheng X, Lian H, Qin C. Peroxisome proliferator-activated receptor-γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk. Int J Clin Exp Med. 2015;8:4066–72.
    1. Mao Q, Guo H, Gao L, Wang H, Ma X. Peroxisome proliferator-activated receptor γ2 Pro12Ala (rs1801282) polymorphism and breast cancer susceptibility: a meta-analysis. Mol Med Rep. 2013;8:1773–8. doi: 10.3892/mmr.2013.1735.
    1. Paltoo D, Woodson K, Taylor P, Albanes D, Virtamo J, Tangrea J. Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma (PPAR-γ) gene and risk of prostate cancer among men in a large cancer prevention study. Cancer Lett. 2003;191:67–74. doi: 10.1016/S0304-3835(02)00617-1.
    1. Freedland SJ, Aronson WJ. Examining the relationship between obesity and prostate cancer. Rev Urol. 2004;6:73–81.
    1. Rivera-Izquierdo M, Pérez de Rojas J, Martínez-Ruiz V, Pérez-Gómez B, Sánchez MJ, Khan KS, et al. Obesity as a risk factor for prostate cancer mortality: a systematic review and dose-response meta-analysis of 280,199 patients. Cancers. 2021;13:4169.
    1. Ferrucci D, Silva SP, Rocha A, Nascimento L, Vieira AS, Taboga SR, et al. Dietary fatty acid quality affects systemic parameters and promotes prostatitis and pre-neoplastic lesions. Sci Rep. 2019;9:19233. doi: 10.1038/s41598-019-55882-5.
    1. Edwards IJ, O’Flaherty JT. Omega-3 fatty acids and PPARgamma in cancer. PPAR Res. 2008;2008:358052. doi: 10.1155/2008/358052.
    1. Sun H, Berquin IM, Owens RT, O’Flaherty JT, Edwards IJ. Peroxisome proliferator-activated receptor gamma-mediated up-regulation of syndecan-1 by n-3 fatty acids promotes apoptosis of human breast cancer cells. Cancer Res. 2008;68:2912–9. doi: 10.1158/0008-5472.CAN-07-2305.
    1. Edwards IJ, Berquin IM, Sun H, O’Flaherty JT, Daniel LW, Thomas MJ, et al. Differential effects of delivery of omega-3 fatty acids to human cancer cells by low-density lipoproteins versus albumin. Clin Cancer Res. 2004;10:8275–83. doi: 10.1158/1078-0432.CCR-04-1357.
    1. Ha X, Wang J, Chen K, Deng Y, Zhang X, Feng J, et al. Free fatty acids promote the development of prostate cancer by upregulating peroxisome proliferator-activated receptor gamma. Cancer Manag Res. 2020;12:1355–69. doi: 10.2147/CMAR.S236301.
    1. Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, et al. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA. 1994;91:7355–9. doi: 10.1073/pnas.91.15.7355.
    1. Rosen CJ. The rosiglitazone story—lessons from an FDA Advisory Committee meeting. N Engl J Med. 2007;357:844–6. doi: 10.1056/NEJMp078167.
    1. Sohda T, Kawamatsu Y, Fujita T, Meguro K, Ikeda H. [Discovery and development of a new insulin sensitizing agent, pioglitazone] Yakugaku Zasshi. 2002;122:909–18. doi: 10.1248/yakushi.122.909.
    1. Brusotti G, Montanari R, Capelli D, Cattaneo G, Laghezza A, Tortorella P, et al. Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis. Sci Rep. 2017;7:5777. doi: 10.1038/s41598-017-05666-6.
    1. Elix CC, Salgia MM, Otto-Duessel M, Copeland BT, Yoo C, Lee M, et al. Peroxisome proliferator-activated receptor gamma controls prostate cancer cell growth through AR-dependent and independent mechanisms. Prostate. 2020;80:162–72. doi: 10.1002/pros.23928.
    1. Zaytseva YY, Wallis NK, Southard RC, Kilgore MW. The PPARgamma antagonist T0070907 suppresses breast cancer cell proliferation and motility via both PPARgamma-dependent and -independent mechanisms. Anticancer Res. 2011;31:813–23.
    1. Al-Jameel W, Gou X, Forootan SS, Al Fayi MS, Rudland PS, Forootan FS, et al. Inhibitor SBFI26 suppresses the malignant progression of castration-resistant PC3-M cells by competitively binding to oncogenic FABP5. Oncotarget. 2017;8:31041–56. doi: 10.18632/oncotarget.16055.
    1. Nakano R, Kurosaki E, Yoshida S, Yokono M, Shimaya A, Maruyama T, et al. Antagonism of peroxisome proliferator-activated receptor gamma prevents high-fat diet-induced obesity in vivo. Biochem Pharmacol. 2006;72:42–52. doi: 10.1016/j.bcp.2006.03.023.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever