PPARα Activation Sensitizes Cancer Cells to Epigallocatechin-3-Gallate (EGCG) Treatment via Suppressing Heme Oxygenase-1

Epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent of green tea, is a potent antioxidant that may have potential therapeutic applications for the treatment of many disorders, including cancer. Peroxisome proliferator-activated receptor-alpha (PPAR alpha) has been shown to play a key role in diverse metabolic and cellular functions. PPAR alpha modulates target gene expression by binding to specific regions on the DNA of target genes. The effects and mechanisms of PPAR alpha activation on EGCG efficacy have not yet been analyzed in cancer cells. We found that when cancer cells were exposed to EGCG, the expression of PPAR alpha was increased at the protein level in a dose-dependent manner. The PPAR alpha agonist clofibrate blocked cytoprotective heme oxygenase-1 (HO-1) induction and sensitized multiple types of cancer cells to EGCG-induced cell death. Conversely, the PPAR alpha inhibitor G6471 and PPAR alpha siRNA increased HO-1 expression. Electro-mobility shift assays (EMSA) and in vivo chromatin immunoprecipitation (ChIP) confirmed that PPAR alpha interacts with the peroxisome proliferator-responsive element of the HO-1 promoter. Moreover, cell death induced by EGCG plus clofibrate was partially reversed by HO-1 overexpression in PANC1 cells. These results indicate that PPAR alpha is a direct and negative regulator of HO-1 induced by EGCG and confers cell susceptibility to EGCG.