Thiazolidinediones regulate expression of cell cycle proteins in human prostate cancer cells via PPARγ-dependent and PPARγ-independent pathways

Thiazolidinediones (TZDs) are peroxisome proliferator activated receptor gamma (PPAR gamma) ligands that have been reported to reduce proliferation of human prostate cancer cells. However, the mechanisms by which TZDs inhibit prostate cancer cell proliferation are not fully understood. In addition, it is not known if the anti-proliferative effects of TZDs require activation of PPAR. or are mediated by PPAR gamma-independent pathways. The goals of this study were to assess whether TZDs regulate expression of proteins that control the transition from G(1) to S phase of the cell cycle and define the role of PPAR. in these TZD-induced responses in androgen-independent human prostate cancer cell lines. Western blot analysis revealed that growth inhibitory concentrations of the TZDs rosiglitazone and ciglitazone induced expression of the cyclin dependent kinase inhibitor p21 and decreased cyclin D1 levels in the androgen independent PC-3 cell line. Phosphorylation of retinoblastoma protein at Serine 780 was also reduced in PC-3 cells exposed to ciglitazone. Furthermore, growth inhibitory concentrations of ciglitazone increased p21 and lowered cyclin D1 expression within C4-2 cells. PPAR gamma-directed siRNAs inhibited the ability of rosiglitazone to regulate expression of cyclin D1 and p21. However, knockdown of PPAR. did not significantly reduce ciglitazone-induced alterations in cyclin D1 and p21. Furthermore PPAR. siRNA did not prevent inhibition of PC-3 cell proliferation by either TZD. Thus, activation of PPAR gamma is involved in rosiglitazone-induced alterations in cell cycle protein expression. However, the alterations in protein expression and proliferation induced by ciglitazone occur primarily via PPAR gamma-independent signaling pathways.