Clofibrate induces heme oxygenase 1 expression through a PPARα-independent mechanism in human cancer cells.

BACKGROUND AND AIMS Clofibrate, an established PPARα ligand, has recently been shown to have anticancer activity yet its mechanisms of action remain to be characterized. This study examined the effect of clofibrate on heme oxygenase-1 (HO-1) gene expression in A2780 (human ovarian cancer) and DU145 (human prostate cancer) cells. METHODS AND RESULTS We demonstrate that clofibrate induces HO-1 expression in a concentration- and time-dependent manner. The induction of HO-1 by clofibrate was detected at both mRNA and protein levels and the HO-1 gene promoter activity was also dramatically induced by clofibrate, indicating that clofibrate up-regulates HO-1 gene transcription. Surprisingly, the induction of HO-1 by clofibrate was mediated by the Nrf2 signaling pathway, not by the PPARα pathway. This was primarily demonstrated by siRNA knockdown of Nrf2 expression that significantly attenuated clofibrate-induced HO-1 gene transcription, and siRNA knockdown of PPARα that had no effect on clofibrate-induced HO-1 promoter activity. Furthermore, deletion of the antioxidant response elements (AREs) in the HO-1 gene promoter diminished clofibrate-induced HO-1 transcription and deletion of the PPAR response elements (PPREs) had no such effect. Likewise, application of PPARα antagonists had no effect on clofibrate-induced HO-1 expression. CONCLUSION Clofibrate induces HO-1 gene expression in cancer cells through a PPARα-independent mechanism and the Nrf2 signaling pathway is indispensible for this induction.