EGR-1/Bax pathway plays a role in vitamin E ?-tocotrienol-induced apoptosis in pancreatic cancer cells.

ABSTRACT: The anticancer activity of ?-tocotrienol, a bioactive vitamin E present in whole grain cereals, annatto beans and palm fruit, is strongly dependent on its effect on the induction of apoptosis. ?-Tocotrienol-induced apoptosis is associated with consistent induction in the expression of the proapoptotic protein Bcl-2-associated X protein (Bax). The molecular mechanism by which ?-tocotrienol regulates Bax expression is unknown. We carried out a DNA microarray study that identified ?-tocotrienol induction of the zinc finger transcription factor EGR-1 in pancreatic cancer cells. Here, we provide evidence linking ?-tocotrienol-induced apoptosis in pancreatic cancer cells to EGR-1 regulation of Bax expression. Forced expression of EGR-1 induces Bax expression and apoptosis in pancreatic cancer cells. In contrast, knockdown of ?-tocotrienol-induced EGR-1 by small interfering RNA attenuated ?-tocotrienol-induced Bax expression and reduced ?-tocotrienol-induced apoptosis. Further analyses showed that de novo protein synthesis was not required for ?-tocotrienol-induced EGR-1 expression, suggesting a direct effect of ?-tocotrienol on EGR-1 expression. Furthermore, a chromatin immunoprecipitation assay demonstrated that EGR-1 binds to the Bax gene promoter. Finally, ?-tocotrienol treatment induced Bax expression and activated EGR-1 in the pancreatic neoplastic cells of the PDX-Cre Kras genetically engineered model of pancreatic cancer. Our study provides the first evidence for EGR-1 as a direct target of vitamin E ?-tocotrienol, suggesting that EGR-1 may act as a proapoptotic factor in pancreatic cancer cells via induction of Bax.

SUBMITTER: Wang C 

PROVIDER: S-EPMC4576995 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature