Nrf2-induced antiapoptotic Bcl-xL protein enhances cell survival and drug resistance.

In this study, we investigated the role of Nrf2 in the regulation of antiapoptotic Bcl-xL protein and its effect on cellular apoptosis. Treatment of mouse Hepa-1 cells with the antioxidant tert-butylhydroquinone led to the induction of Bcl-xL gene expression. Promoter mutagenesis, transfection, and chromatin immunoprecipitation assays identified an ARE between nucleotides -608 and -600 in the forward strand of the proximal Bcl-xL promoter that bound to Nrf2 and led to increased Bcl-xL gene expression. In addition, short interfering RNA (siRNA) inhibition and overexpression of Nrf2 led to a respective decrease and increase in Bcl-xL gene expression. These results implicated Nrf2 in the regulation of expression and induction of Bcl-xL protein. Nrf2-mediated expression of Bcl-xL protein downregulated Bax and decreased caspase 3/7 activity. SiRNA inhibition of both Nrf2 and Bcl-xL increased the susceptibility of cancer cells to etoposide-mediated cell death and reduced cell survival. Moreover, dysfunctional/mutant INrf2 (inhibitor of Nrf2) in human lung cancer cells failed to degrade Nrf2, resulting in increased Bcl-xL levels and increased cell survival. These data provide the first evidence of Nrf2 in the control of Bcl-xL expression and apoptotic cell death with implications for antioxidant protection, survival of cancer cells, and drug resistance. PMID: 23275004 [PubMed - as supplied by publisher]
Source: Free Radical Biology and Medicine - Category: Biology Authors: Tags: Free Radic Biol Med Source Type: research