PPARgamma-independent induction of growth arrest and apoptosis in prostate and bladder carcinoma.
BACKGROUND
Although PPARgamma antagonists have shown considerable pre-clinical efficacy, recent studies suggest PPARgamma ligands induce PPARgamma-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 PPARgamma 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 PPARgamma 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.


CONCLUSIONS
Troglitazone and 15dPGJ2 inhibit growth of prostate and bladder carcinoma cell lines through different mechanisms and the effects of both agents are PPARgamma-independent.
Chaffer
Christine L
CL
Bernard O'Brien Institute of Microsurgery, Victoria, Australia. c.chaffer@pgrad.unimelb.edu.au
Thomas
David M
DM
Thompson
Erik W
EW
Williams
Elizabeth D
ED
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology* / Q000627:therapeutic use; D053938:DNA Fragmentation; D006801:Humans; D008024:Ligands; D008297:Male; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D000077288:Troglitazone; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
C477819:15-deoxyprostaglandin J2; D000970:Antineoplastic Agents; D002839:Chromans; D008024:Ligands; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases; D000077288:Troglitazone; D015230:Prostaglandin D2