Abstract
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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alitretinoin
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Carcinoma, Transitional Cell / metabolism*
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Carcinoma, Transitional Cell / pathology
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Carrier Proteins / metabolism
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Cell Death
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Chromans / pharmacology
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Cyclin D1 / metabolism
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / metabolism
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DNA / biosynthesis
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DNA, Complementary / metabolism
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Dose-Response Relationship, Drug
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Fatty Acid-Binding Protein 7
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Fatty Acid-Binding Proteins
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G1 Phase / drug effects
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Humans
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Immunoblotting
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In Situ Hybridization
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Ligands
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Luciferases / metabolism
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Myelin P2 Protein / metabolism
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Neoplasm Proteins*
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Nicotinic Acids / pharmacology
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Receptors, Cytoplasmic and Nuclear / biosynthesis*
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Retinoic Acid / biosynthesis
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Receptors, Retinoic Acid / genetics
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Retinoid X Receptors
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Ribonucleases / metabolism
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Tetrahydronaphthalenes / pharmacology
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Thiazoles / pharmacology
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Thiazolidinediones*
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Transcription Factors / biosynthesis*
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Transcription Factors / genetics
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Transcriptional Activation
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Transfection
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Tretinoin / pharmacology
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Troglitazone
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Tumor Cells, Cultured
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Tumor Suppressor Proteins*
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Urinary Bladder Neoplasms / metabolism*
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Urinary Bladder Neoplasms / pathology
Substances
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Antineoplastic Agents
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CDKN1A protein, human
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Carrier Proteins
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Chromans
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA, Complementary
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FABP7 protein, human
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Fatty Acid-Binding Protein 7
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Fatty Acid-Binding Proteins
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Ligands
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Myelin P2 Protein
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Neoplasm Proteins
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Nicotinic Acids
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Receptors, Cytoplasmic and Nuclear
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Receptors, Retinoic Acid
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Retinoid X Receptors
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Tetrahydronaphthalenes
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Thiazoles
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Thiazolidinediones
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Transcription Factors
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Tumor Suppressor Proteins
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Cyclin D1
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Alitretinoin
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Tretinoin
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DNA
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2,4-thiazolidinedione
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Luciferases
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Ribonucleases
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Troglitazone
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LG 100268