Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in human transitional bladder cancer and its role in inducing cell death.
The present study examined the expression and role of the thiazolidinedione (TZD)-activated transcription factor, peroxisome proliferator-activated receptor gamma (PPARgamma), in human bladder cancers. In situ hybridization shows that PPARgamma mRNA is highly expressed in all human transitional epithelial cell cancers (TCCa's) studied (n=11). PPARgamma was also expressed in five TCCa cell lines as determined by RNase protection assays and immunoblot. Retinoid X receptor alpha (RXRalpha), a 9-cis-retinoic acid stimulated (9-cis-RA) heterodimeric partner of PPARgamma, was also co-expressed in all TCCa tissues and cell lines. Treatment of the T24 bladder cancer cells with the TZD PPARgamma agonist troglitazone, dramatically inhibited 3H-thymidine incorporation and induced cell death. Addition of the RXRalpha ligands, 9-cis-RA or LG100268, sensitized T24 bladder cancer cells to the lethal effect of troglitazone and two other PPAR- activators, ciglitazone and 15-deoxy-delta(12,14)-PGJ2 (15dPGJ(2)). Troglitazone treatment increased expression of two cyclin-dependent kinase inhibitors, p21(WAF1/CIP1) and p16(INK4), and reduced cyclin D1 expression, consistent with G1 arrest. Troglitazone also induced an endogenous PPARgamma target gene in T24 cells, adipocyte-type fatty acid binding protein (A-FABP), the expression of which correlates with bladder cancer differentiation. In situ hybridization shows that A-FABP expression is localized to normal uroepithelial cells as well as some TCCa's. Taken together, these results demonstrate that PPARgamma is expressed in human TCCa where it may play a role in regulating TCCa differentiation and survival, thereby providing a potential target for therapy of uroepithelial cancers.
Division of Nephrology, Veterans Administration Medical Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Y F
YF
Guan
Y H
YH
Zhang
R M
RM
Breyer
L
L
Davis
M D
MD
Breyer
D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002295:Carcinoma, Transitional Cell / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D016923:Cell Death; D002839:Chromans / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D017403:In Situ Hybridization; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D018996:Myelin P2 Protein / Q000378:metabolism; D009363:Neoplasm Proteins; D009539:Nicotinic Acids / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics; D047488:Retinoid X Receptors; D012260:Ribonucleases / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D000077288:Troglitazone; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D002352:Carrier Proteins; D002839:Chromans; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018076:DNA, Complementary; C107608:FABP7 protein, human; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D008024:Ligands; D018996:Myelin P2 Protein; D009363:Neoplasm Proteins; D009539:Nicotinic Acids; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D000077556:Alitretinoin; D014212:Tretinoin; D004247:DNA; C089946:2,4-thiazolidinedione; D008156:Luciferases; D012260:Ribonucleases; D000077288:Troglitazone; C095104:LG 100268