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-α (PPARα) has been shown to play a key role in diverse metabolic and cellular functions. PPARα modulates target gene expression by binding to specific regions on the DNA of target genes. The effects and mechanisms of PPARα 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 PPARα was increased at the protein level in a dose-dependent manner. The PPARα agonist clofibrate blocked cytoprotective heme oxygenase-1 (HO-1) induction and sensitized multiple types of cancer cells to EGCG-induced cell death. Conversely, the PPARα inhibitor G6471 and PPARα siRNA increased HO-1 expression. Electro-mobility shift assays (EMSA) and in vivo chromatin immunoprecipitation (ChIP) confirmed that PPARα 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 PPARα is a direct and negative regulator of HO-1 induced by EGCG and confers cell susceptibility to EGCG.
a School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection , Soochow University , Suzhou , China.
Shuyu
S
Zhang
Xiaodong
X
Yang
Judong
J
Luo
Xin
X
Ge
Wanping
W
Sun
Hong
H
Zhu
Weiping
W
Zhang
Jianping
J
Cao
Yinglong
Y
Hou
D000975:Antioxidants / Q000494:pharmacology; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D013662:Tea / Q000737:chemistry
D000975:Antioxidants; D047493:PPAR alpha; D034741:RNA, Small Interfering; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1