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BMC Cancer

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Open Access 01-12-2006 | Research article

PPARγ-independent induction of growth arrest and apoptosis in prostate and bladder carcinoma

Authors: Christine L Chaffer, David M Thomas, Erik W Thompson, Elizabeth D Williams

Published in: BMC Cancer | Issue 1/2006

Abstract

Background

Although PPARγ antagonists have shown considerable pre-clinical efficacy, recent studies suggest PPARγ ligands induce PPARγ-independent effects. There is a need to better define such effects to permit rational utilization of these agents.

Methods

We have studied the effects of a range of endogenous and synthetic PPARγ ligands on proliferation, growth arrest (FACS analysis) and apoptosis (caspase-3/7 activation and DNA fragmentation) in multiple prostate carcinoma cell lines (DU145, PC-3 and LNCaP) and in a series of cell lines modelling metastatic transitional cell carcinoma of the bladder (TSU-Pr1, TSU-Pr1-B1 and TSU-Pr1-B2).

Results

15-deoxy-prostaglandin J₂ (15dPGJ2), troglitazone (TGZ) and to a lesser extent ciglitazone exhibited inhibitory effects on cell number; the selective PPARγ antagonist GW9662 did not reverse these effects. Rosiglitazone and pioglitazone had no effect on proliferation. In addition, TGZ induced G0/G1 growth arrest whilst 15dPGJ2 induced apoptosis.

Conclusion

Troglitazone and 15dPGJ2 inhibit growth of prostate and bladder carcinoma cell lines through different mechanisms and the effects of both agents are PPARγ-independent.

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Yoshimura R, Matsuyama M, Segawa Y, Hase T, Mitsuhashi M, Tsuchida K, Wada S, Kawahito Y, Sano H, Nakatani T: Expression of peroxisome proliferator-activated receptors (PPARs) in human urinary bladder carcinoma and growth inhibition by its agonists. Int J Cancer. 2003, 104: 597-602. 10.1002/ijc.10980.CrossRefPubMed

Kubota T, Koshizuka K, Williamson EA, Asou H, Said JW, Holden S, Miyoshi I, Koeffler HP: 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: 3344-3352.PubMed

Segawa Y, Yoshimura R, Hase T, Nakatani T, Wada S, Kawahito Y, Kishimoto T, Sano H: Expression of peroxisome proliferator-activated receptor (PPAR) in human prostate cancer. Prostate. 2002, 51: 108-116. 10.1002/pros.10058.CrossRefPubMed

DuBois RN, Gupta R, Brockman J, Reddy BS, Krakow SL, Lazar MA: The nuclear eicosanoid receptor, PPARgamma, is aberrantly expressed in colonic cancers. Carcinogenesis. 1998, 19: 49-53. 10.1093/carcin/19.1.49.CrossRefPubMed

Panigrahy D, Singer S, Shen LQ, Butterfield CE, Freedman DA, Chen EJ, Moses MA, Kilroy S, Duensing S, Fletcher C, Fletcher JA, Hlatky L, Hahnfeldt P, Folkman J, Kaipainen A: PPAR gamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. J Clin Invest. 2002, 110: 923-932. 10.1172/JCI200215634.CrossRefPubMedPubMedCentral

Elstner E, Muller C, Koshizuka K, Williamson EA, Park D, Asou H, Shintaku P, Said JW, Heber D, Koeffler HP: Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci U S A. 1998, 95: 8806-8811. 10.1073/pnas.95.15.8806.CrossRefPubMedPubMedCentral

Sarraf P, Mueller E, Jones D, King FJ, DeAngelo DJ, Partridge JB, Holden SA, Chen LB, Singer S, Fletcher C, Spiegelman BM: Differentiation and reversal of malignant changes in colon cancer through PPARgamma. Nat Med. 1998, 4: 1046-1052. 10.1038/2030.CrossRefPubMed

Han S, Roman J: Suppression of prostaglandin E2 receptor subtype EP2 by PPARgamma ligands inhibits human lung carcinoma cell growth. Biochem Biophys Res Commun. 2004, 314: 1093-1099. 10.1016/j.bbrc.2004.01.007.CrossRefPubMed

Koeffler HP: Peroxisome proliferator-activated receptor gamma and cancers. Clin Cancer Res. 2003, 9: 1-9.PubMed

10.

Fajas L, Auboeuf D, Raspe E, Schoonjans K, Lefebvre AM, Saladin R, Najib J, Laville M, Fruchart JC, Deeb S, Vidal-Puig A, Flier J, Briggs MR, Staels B, Vidal H, Auwerx J: The organization, promoter analysis, and expression of the human PPARgamma gene. J Biol Chem. 1997, 272: 18779-18789. 10.1074/jbc.272.30.18779.CrossRefPubMed

11.

Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM: PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell. 1999, 4: 611-617. 10.1016/S1097-2765(00)80211-7.CrossRefPubMed

12.

Saltiel AR, Olefsky JM: Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes. 1996, 45: 1661-1669.CrossRefPubMed

13.

Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM: A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell. 1995, 83: 813-819. 10.1016/0092-8674(95)90194-9.CrossRefPubMed

14.

Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM: 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell. 1995, 83: 803-812. 10.1016/0092-8674(95)90193-0.CrossRefPubMed

15.

Shiau CW, Yang CC, Kulp SK, Chen KF, Chen CS, Huang JW: Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 functions independently of PPARgamma. Cancer Res. 2005, 65: 1561-1569. 10.1158/0008-5472.CAN-04-1677.CrossRefPubMed

16.

Sato H, Ishihara S, Kawashima K, Moriyama N, Suetsugu H, Kazumori H, Okuyama T, Rumi MA, Fukuda R, Nagasue N, Kinoshita Y: Expression of peroxisome proliferator-activated receptor (PPAR)gamma in gastric cancer and inhibitory effects of PPARgamma agonists. Br J Cancer. 2000, 83: 1394-1400. 10.1054/bjoc.2000.1457.CrossRefPubMedPubMedCentral

17.

Guan YF, Zhang YH, Breyer RM, Davis L, Breyer MD: Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in human transitional bladder cancer and its role in inducing cell death. Neoplasia. 1999, 1: 330-339. 10.1038/sj.neo.7900050.CrossRefPubMedPubMedCentral

18.

Bae MA, Rhee H, Song BJ: Troglitazone but not rosiglitazone induces G1 cell cycle arrest and apoptosis in human and rat hepatoma cell lines. Toxicol Lett. 2003, 139: 67-75. 10.1016/S0378-4274(02)00468-X.CrossRefPubMed

19.

Baek SJ, Wilson LC, Hsi LC, Eling TE: Troglitazone, a peroxisome proliferator-activated receptor gamma (PPAR gamma ) ligand, selectively induces the early growth response-1 gene independently of PPAR gamma. A novel mechanism for its anti-tumorigenic activity. J Biol Chem. 2003, 278: 5845-5853. 10.1074/jbc.M208394200.CrossRefPubMed

20.

Lennon AM, Ramauge M, Dessouroux A, Pierre M: MAP kinase cascades are activated in astrocytes and preadipocytes by 15-deoxy-Delta(12-14)-prostaglandin J(2) and the thiazolidinedione ciglitazone through peroxisome proliferator activator receptor gamma-independent mechanisms involving reactive oxygenated species. J Biol Chem. 2002, 277: 29681-29685. 10.1074/jbc.M201517200.CrossRefPubMed

21.

Perez-Ortiz JM, Tranque P, Vaquero CF, Domingo B, Molina F, Calvo S, Jordan J, Cena V, Llopis J: Glitazones differentially regulate primary astrocyte and glioma cell survival. Involvement of reactive oxygen species and peroxisome proliferator-activated receptor-gamma. J Biol Chem. 2004, 279: 8976-8985. 10.1074/jbc.M308518200.CrossRefPubMed

22.

Nikitakis NG, Siavash H, Hebert C, Reynolds MA, Hamburger AW, Sauk JJ: 15-PGJ2, but not thiazolidinediones, inhibits cell growth, induces apoptosis, and causes downregulation of Stat3 in human oral SCCa cells. Br J Cancer. 2002, 87: 1396-1403. 10.1038/sj.bjc.6600618.CrossRefPubMedPubMedCentral

23.

Okano H, Shiraki K, Inoue H, Yamanaka Y, Kawakita T, Saitou Y, Yamaguchi Y, Enokimura N, Yamamoto N, Sugimoto K, Murata K, Nakano T: 15-deoxy-delta-12-14-PGJ2 regulates apoptosis induction and nuclear factor-kappaB activation via a peroxisome proliferator-activated receptor-gamma-independent mechanism in hepatocellular carcinoma. Lab Invest. 2003, 83: 1529-1539. 10.1097/01.LAB.0000092233.50246.F7.CrossRefPubMed

24.

Clay CE, Monjazeb A, Thorburn J, Chilton FH, High KP: 15-Deoxy-delta12,14-prostaglandin J2-induced apoptosis does not require PPARgamma in breast cancer cells. J Lipid Res. 2002, 43: 1818-1828. 10.1194/jlr.M200224-JLR200.CrossRefPubMed

25.

Kim EJ, Park KS, Chung SY, Sheen YY, Moon DC, Song YS, Kim KS, Song S, Yun YP, Lee MK, Oh KW, Yoon do Y, Hong JT: Peroxisome proliferator-activated receptor-gamma activator 15-deoxy-Delta12,14-prostaglandin J2 inhibits neuroblastoma cell growth through induction of apoptosis: association with extracellular signal-regulated kinase signal pathway. J Pharmacol Exp Ther. 2003, 307: 505-517. 10.1124/jpet.103.053876.CrossRefPubMed

26.

Bruemmer D, Yin F, Liu J, Berger JP, Sakai T, Blaschke F, Fleck E, Van Herle AJ, Forman BM, Law RE: Regulation of the growth arrest and DNA damage-inducible gene 45 (GADD45) by peroxisome proliferator-activated receptor gamma in vascular smooth muscle cells. Circ Res. 2003, 93: e38-47. 10.1161/01.RES.0000088344.15288.E6.CrossRefPubMed

27.

Cancer in Australia 2000. In: AIHW & Australasian Association of Cancer Registries. 2003

28.

Mueller E, Smith M, Sarraf P, Kroll T, Aiyer A, Kaufman DS, Oh W, Demetri G, Figg WD, Zhou XP, Eng C, Spiegelman BM, Kantoff PW: Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. Proc Natl Acad Sci U S A. 2000, 97: 10990-10995. 10.1073/pnas.180329197.CrossRefPubMedPubMedCentral

29.

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: 5494-5498.PubMed

30.

Saez E, Olson P, Evans RM: Genetic deficiency in Pparg does not alter development of experimental prostate cancer. Nat Med. 2003, 9: 1265-1266. 10.1038/nm928.CrossRefPubMed

31.

Haslmayer P, Thalhammer T, Jager W, Aust S, Steiner G, Ensinger C, Obrist P: The peroxisome proliferator-activated receptor gamma ligand 15-deoxy-Delta12,14-prostaglandin J2 induces vascular endothelial growth factor in the hormone-independent prostate cancer cell line PC 3 and the urinary bladder carcinoma cell line 5637. Int J Oncol. 2002, 21: 915-920.PubMed

32.

Nakashiro KI, Hayashi Y, Kita A, Tamatani T, Chlenski A, Usuda N, Hattori K, Reddy JK, Oyasu R: Role of peroxisome proliferator-activated receptor gamma and its ligands in non-neoplastic and neoplastic human urothelial cells. Am J Pathol. 2001, 159: 591-597.CrossRefPubMedPubMedCentral

33.

Butler R, Mitchell SH, Tindall DJ, Young CY: Nonapoptotic cell death associated with S-phase arrest of prostate cancer cells via the peroxisome proliferator-activated receptor gamma ligand, 15-deoxy-delta12,14-prostaglandin J2. Cell Growth Differ. 2000, 11: 49-61.PubMed

34.

Xu Y, Iyengar S, Roberts RL, Shappell SB, Peehl DM: Primary culture model of peroxisome proliferator-activated receptor gamma activity in prostate cancer cells. J Cell Physiol. 2003, 196: 131-143. 10.1002/jcp.10281.CrossRefPubMed

35.

Djakiew D, Pflug BR, Delsite R, Onoda M, Lynch JH, Arand G, Thompson EW: Chemotaxis and chemokinesis of human prostate tumor cell lines in response to human prostate stromal cell secretory proteins containing a nerve growth factor-like protein. Cancer Res. 1993, 53: 1416-1420.PubMed

36.

Sharp JA, Waltham M, Williams ED, Henderson MA, Thompson EW: Transfection of MDA-MB-231 human breast carcinoma cells with bone sialoprotein (BSP) stimulates migration and invasion in vitro and growth of primary and secondary tumors in nude mice. Clin Exp Metastasis. 2004, 21: 19-29. 10.1023/B:CLIN.0000017167.17065.61.CrossRefPubMed

37.

McGahon AJ, Costa Pereira AP, Daly L, Cotter TG: Chemotherapeutic drug-induced apoptosis in human leukaemic cells is independent of the Fas (APO-1/CD95) receptor/ligand system. Br J Haematol. 1998, 101: 539-547. 10.1046/j.1365-2141.1998.00745.x.CrossRefPubMed

38.

Mueller E, Sarraf P, Tontonoz P, Evans RM, Martin KJ, Zhang M, Fletcher C, Singer S, Spiegelman BM: Terminal differentiation of human breast cancer through PPAR gamma. Mol Cell. 1998, 1: 465-470. 10.1016/S1097-2765(00)80047-7.CrossRefPubMed

39.

Turturro F, Friday E, Fowler R, Surie D, Welbourne T: Troglitazone acts on cellular pH and DNA synthesis through a peroxisome proliferator-activated receptor gamma-independent mechanism in breast cancer-derived cell lines. Clin Cancer Res. 2004, 10: 7022-7030. 10.1158/1078-0432.CCR-04-0879.CrossRefPubMed

40.

Yin F, Bruemmer D, Blaschke F, Hsueh WA, Law RE, Herle AJ: Signaling pathways involved in induction of GADD45 gene expression and apoptosis by troglitazone in human MCF-7 breast carcinoma cells. Oncogene. 2004, 23: 4614-4623. 10.1038/sj.onc.1207598.CrossRefPubMed

41.

Shappell SB, Gupta RA, Manning S, Whitehead R, Boeglin WE, Schneider C, Case T, Price J, Jack GS, Wheeler TM, Matusik RJ, Brash AR, Dubois RN: 15S-Hydroxyeicosatetraenoic acid activates peroxisome proliferator-activated receptor gamma and inhibits proliferation in PC3 prostate carcinoma cells. Cancer Res. 2001, 61: 497-503.PubMed

42.

Roth AD, Leisewitz AV, Jung JE, Cassina P, Barbeito L, Inestrosa NC, Bronfman M: PPAR gamma activators induce growth arrest and process extension in B12 oligodendrocyte-like cells and terminal differentiation of cultured oligodendrocytes. J Neurosci Res. 2003, 72: 425-435. 10.1002/jnr.10596.CrossRefPubMed

43.

Farrow B, Evers BM: Activation of PPARgamma increases PTEN expression in pancreatic cancer cells. Biochem Biophys Res Commun. 2003, 301: 50-53. 10.1016/S0006-291X(02)02983-2.CrossRefPubMed

44.

Chintharlapalli S, Papineni S, Baek SJ, Liu S, Safe SH: 1,1-Bis(3'-indolyl)-1-(p-substitutedphenyl)methanes Are Peroxisome Proliferator-Activated Receptor {gamma} Agonists But Decrease HCT-116 Colon Cancer Cell Survival Through Receptor-independent Activation of Early Growth Response-1 and NAG-1. Mol Pharmacol. 2005

45.

Saez E, Tontonoz P, Nelson MC, Alvarez JG, Ming UT, Baird SM, Thomazy VA, Evans RM: Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nat Med. 1998, 4: 1058-1061. 10.1038/2042.CrossRefPubMed

46.

Saez E: PPAR[gamma] signalling exacerbates mammary gland tumor development. Genes Dev. 2004, 18: 528-540. 10.1101/gad.1167804.CrossRefPubMedPubMedCentral

47.

Varley CL, Stahlschmidt J, Lee WC, Holder J, Diggle C, Selby PJ, Trejdosiewicz LK, Southgate J: Role of PPARgamma and EGFR signalling in the urothelial terminal differentiation programme. J Cell Sci. 2004, 117: 2029-2036. 10.1242/jcs.01042.CrossRefPubMed

48.

Drori S, Girnun GD, Tou L, Szwaya JD, Mueller E, Kia X, Shivdasani RA, Spiegelman BM: Hic-5 regulates an epithelial program mediated by PPARgamma. Genes Dev. 2005, 19: 362-375. 10.1101/gad.1240705.CrossRefPubMedPubMedCentral

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/6/53/prepub

Title: PPARγ-independent induction of growth arrest and apoptosis in prostate and bladder carcinoma
Authors: Christine L Chaffer
David M Thomas
Erik W Thompson
Elizabeth D Williams
Publication date: 01-12-2006
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2006
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/1471-2407-6-53

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