The peroxisome proliferator-activated receptor-γ (PPARγ) belongs to the nuclear hormone receptor superfamily, and is expressed in adipose tissue, skeletal muscle, spleen, heart, liver, placenta, lung, and ovary. PPARγ is a critical regulator of inflammation, adipocyte differentiation, glucose homeostasis, and tumorigenesis. The mechanism of PPARγ on tumor suppression is still unclear, but plenty of evidence shows that PPARγ provides new therapeutic targets for cancer. Here we give a review of how PPARγ and its ligands regulate tumorigenesis by different pathways.

Keywords:
PPARγ, Ligands, Tumor suppressor
1.
Wang T, Xu J, Yu X, et al.: Peroxisome proliferator-activated receptor gamma in malignant diseases. Crit Rev Oncol Hematol 2006;58:1-14.
2.
Greene ME, Blumberg B, McBride OW, et al.: Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Expr 1995;4:281-299.
3.
Sundvold H, Lien S: Identification of a novel peroxisome proliferator-activated receptor (PPAR) gamma promoter in man and transactivation by the nuclear receptor RORalpha1. Biochem Biophys Res Commun 2001;287:383-390.
4.
Meirhaeghe A, Fajas L, Gouilleux F, et al.: A functional polymorphism in a STAT5B site of the human PPAR gamma 3 gene promoter affects height and lipid metabolism in a French population. Arterioscler Thromb Vasc Biol 2003;23:289-294.
5.
Skelhorne-Gross G, Reid AL, Apostoli AJ, et al.: Stromal adipocyte PPAR gamma protects against breast tumorigenesis. Carcinogenesis 2012;33:1412-1420.
6.
Ogino S, Shima K, Baba Y, et al.: Colorectal cancer expression of PPARG (peroxisome proliferator-activated receptor-gamma) is associated with good prognosis. Gastroenterology 2009;136:1242-1250.
7.
He Q, Chen J, Lin HL, et al.: Expression of peroxisome proliferator-activated receptor gamma, E-cadherin and matrix metalloproteinases-2 in gastric carcinoma and lymph node metastases. Chin Med J (Engl) 2007;120:1498-1504.
8.
Aldred MA, Morrison C, Gimm O, et al.: Peroxisome proliferator-activated receptor γ is frequently downregulated in a diversity of sporadic nonmedullary thyroid carcinomas. Oncogene 2003;22:3412-3416.
9.
Jung TI, Baek WK, Suh SI, et al.: Down-regulation of peroxisome proliferator-activated receptor γ in human cervical carcinoma. Gynecol Oncol 2005;97:365-373.
10.
Terashita Y, Sasaki H, Haruki N, et al.: Decreased peroxisome proliferator-activated receptor γ gene expression is correlated with poor prognosis in patients with esophageal cancer. Jpn J Clin Oncol 2002;32:238-243.
11.
Rogenhofer S, Ellinger J, Kahl P, et al.: Enhanced expression of peroxisome proliferate-activated receptor gamma (PPAR-gamma) in advanced prostate cancer. Anticancer Res 2012;32:3479-3483.
12.
Zhang GY, Ahmed N, Riley C, et al.: Enhanced expression of peroxisome proliferator-activated receptor gamma in epithelial ovarian carcinoma. Br J Cancer 2005;92:113-119.
13.
Kubota T, Koshizuka K, Williamson EA, Asou H, Said JW, Holden S, et al.: Ligand for peroxisome proliferator-activated receptor γ (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res 1998;58:3344-3352.
14.
Hase T, Yoshimura R, Mitsuhashi M, et al.: Expression of peroxisome proliferator- activated receptors in human testicular cancer and growth inhibition by its agonists. Urology 2002;60:542-547.
15.
Ray DM, Akbiyik F, Phipps RP: The peroxisome proliferator-activated receptor gamma (PPAR gamma) ligands 15-deoxy-Delta12.14-prostaglandin J2 and ciglitazone induce human B lymphocyte and B cell lymphoma apoptosis by PPAR gamma-independent mechanisms. J Immunol 2006;177: 5068-5076.
16.
Lu Y, Zhou Q, Zhong F, et al.: 15-deoxy-L-prostaglandin J2 modulates lipopolysaccharide-induced chemokine expression by blocking nuclear factor-κB activation via peroxisome proliferator activated receptor-γ-independent mechanism in renal tubular epithelial cells. Nephron Exp Nephrol 2013;123:1-10.
17.
Fujita M, Tohji C, Honda Y, et al.: Cytotoxicity of 15-deoxy-C(12.14)-prostaglandin J(2) through PPARγ-independent pathway and the involvement of the JNK and Akt pathway in renal cell carcinoma. Int J Med Sci 2012;9:555-566.
18.
Park EJ, Park SY, Jou EH, Jou I: 15d-PGJ2 and rosiglitazone suppress Janus kinase-STAT inflammatory signaling through induction of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 in glia. J Biol Chem 2003;278:14747-14752.
19.
Keshamouni VG, Reddy RC, Arenberg DA, et al.: Peroxisome proliferator-activated receptor-gamma activation inhibits tumor progression in non-small-cell lung cancer. Oncogene 2004;23:100-108.
20.
Al-Alem L, Southard RC, Kilgore MW, Curry TE: Specific thiazolidinediones inhibit ovarian cancer cell line proliferation and cause cell cycle arrest in a PPARγ independent manner. PLoS One 2011;6:e16179.
21.
Akinyeke TO, Stewart LV: Troglitazone suppresses c-myc levels in human prostate cancer cells via a PPAR γ-independent mechanism. Cancer Biol Ther 2011;11:1046-1058.
22.
Heaney A P, Fernando M, Melmed S: PPAR-gamma receptor ligands: novel therapy for pituitary adenomas. J Clin Invest 2003;111:1381-1388.
23.
Vitale G, Zappavigna S, Marra M, et al.: The PPARγ agonist troglitazone antagonizes survival pathways induced by STAT-3 in recombinant interferon-β treated pancreatic cancer cells. Bio-technol Adv 2012;30:169-184.
24.
Milkevitch M, Beardsley NJ, Delikatny EJ: Phenylbutyrate induces apoptosis and lipid accumulations via a peroxisome proliferator-activated receptor gamma-dependent pathway. NMR Biomed 2010;23:473-479.
25.
Bonofiglio D, Gabriele S, Aquila S, et al.: Peroxisome proliferator-activated receptor gamma activates fas ligand gene promoter inducing apoptosis in human breast cancer cells. Breast Cancer Res Treat 2009;113:423-434.
26.
Green DR: Apoptotic pathways: the roads to ruin. Cell 1998;94:695-698.
27.
Aljada A, O'Connor L, Fu YY, Mousa SA: PPAR γ ligands, rosiglitazone and pioglitazone, inhibit bFGF-and VEGF-mediated angiogenesis. Angiogenesis 2008;11:361-367.
28.
Goetze S, Eilers F, Bungenstock A, et al.: PPAR activators inhibit endothelial cell migration by targeting Akt. Biochem Biophys Res Commun 2002;293:1431-1437.
29.
Dicitore A, Caraglia M, Colao A, et al.: Combined treatment with PPAR-γ agonists in pancreatic cancer: a glimmer of hope for cancer therapy? Curr Cancer Drug Targets 2013;13:460-471.
30.
Jiang Y, Huang Y, Cheng C, et al.: Combination of thiazolidinedione and hydralazine suppresses proliferation and induces apoptosis by PPARγ up-expression in MDA-MB-231 cells. Exp Mol Pathol 2011;91:768-774.
31.
Yokoyama Y, Xin B, Shigeto T, Mizunuma H: Combination of ciglitazone, a peroxisome proliferator-activated receptor gamma ligand, and cisplatin enhances the inhibition of growth of human ovarian cancers. J Cancer Res Clin Oncol 2011;137: 1219-1228.
32.
Koga H, Selvendiran K, Sivakumar R, et al.: PPARγ potentiates anticancer effects of gemcitabine on human pancreas cancer cells. Int J Oncol 2012;40:679-685.
33.
Kim BM, Maeng K, Lee KH, Hong SH: Combined treatment with the Cox-2 inhibitor niflumic acid and PPARγ ligand ciglitazone induces ER stress/caspase-8-mediated apoptosis in human lung cancer cells. Cancer Lett 2011;300:124-144.
34.
Lee SY, Hur GY, Jung KH, et al.: PPAR-gamma agonist increase gefitinib's antitumor activity through PTEN expression. Lung Cancer 2006;51: 297-301.
35.
Sun WH, Chen GS, Ou XL, et al.: Inhibition of COX-2 and activation of peroxisome proliferator-activated receptor gamma synergistically inhibits proliferation and induces apoptosis of human pancreas carcinoma cells. Cancer Lett 2009;275:247-255.
36.
Yamamoto Y, Fujita M, Koma H, et al.: 15-Deoxy-a12.14-prostaglandin J2 enhanced the anti-tumor activity of camptothecin against renal cell carcinoma independently of topoisomerase-II and PPARγ pathways. Biochem Biophys Res Common 2011;410:563-567.
37.
Joazeiro CA, Weissman AM: RING finger proteins: mediators of ubiquitin ligase activity. Cell 2000;102:549-552.
38.
Deshaies RJ, Joazeiro CA: RING domain E3 ubiquitin ligases. Annu Rev Biochem 2009;78:399-434.
39.
Hou Y, Zhang Z, Xu Q, et al.: Inhibitor of growth 4 induces NFκB/p65 ubiquitin-dependent degradation. Oncogene 2013;Epub ahead of print.
40.
Hou Y, Moreau F, Chadee K: PPARγ is an E3 ligase that induces the degradation of NFκB/p65. Nat Commun 2012;3:1300.
41.
Ryan KK, Li B, Bernadette E, et al.: A role for central nervous system PPAR-γ in the regulation of energy balance. Nat Med 2011;17:623-626.
42.
Lu M, Sarruf DA, Talukdar S, et al.: Brain PPARγ promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. Nat Med 2011;17:618-622.
43.
Choi JH, Banks AS, Kamenecka TM, et al.: Anti-diabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation. Nature 2011;477:477-481.
© 2013 S. Karger GmbH, Freiburg
2013
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.