Role of PPARgamma in the control of prostate cancer growth: a new approach for therapy

Abstract

In several cases of prostate cancer, resistance to hormonal therapies is observed. Alternative therapeutic strategies for the treatment of prostate cancer are of great interest. Participation of the nuclear receptor PPARgamma in the physiopathology of the prostate, in particular in prostate cancer has been recently studied. PPARgamma is a member of the hormone nuclear receptor superfamily. As for most members of the family, its activity is regulated by ligands. PPARgamma has been shown to be over-expressed in several cancers, including prostate cancer. In vitro and in vivo studies have demonstrated anti-proliferative and pro-apoptotic actions of the PPARgamma agonists thiazolidinediones, suggesting that PPARgamma could be a promising therapeutical target for the treatment of cancer. No effects of PPARgamma agonists have been observed, however, in a large randomized clinical trial in the "rising PSA" group of prostate cancer patients. This suggests that PPARgamma activity is controled by other factors, in addition to its ligands, in prostate cancer. We have shown that PPARgamma activity is repressed by HDACs. Moreover, PPARgamma activity is enhanced in the presence of HDAC inhibitors. A combination treatment using HDAC inhibitors and PPARgamma agonists results in growth arrest of prostate tumors in mice. Furthermore, the combination therapy inhibits invasion of prostate cancer cells in vivo, through upregulation of the expression of the E-cadherin gene.