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

Abstract

The anticancer activity of δ-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. δ-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 δ-tocotrienol regulates Bax expression is unknown. We carried out a DNA microarray study that identified δ-tocotrienol induction of the zinc finger transcription factor EGR-1 in pancreatic cancer cells. Here, we provide evidence linking δ-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 δ-tocotrienol-induced EGR-1 by small interfering RNA attenuated δ-tocotrienol-induced Bax expression and reduced δ-tocotrienol-induced apoptosis. Further analyses showed that de novo protein synthesis was not required for δ-tocotrienol-induced EGR-1 expression, suggesting a direct effect of δ-tocotrienol on EGR-1 expression. Furthermore, a chromatin immunoprecipitation assay demonstrated that EGR-1 binds to the Bax gene promoter. Finally, δ-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 δ-tocotrienol, suggesting that EGR-1 may act as a proapoptotic factor in pancreatic cancer cells via induction of Bax.

• Authors: Chen Wang, Kazim Husain, Anying Zhang, Barbara A Centeno, Dung-Tsa Chen, Zhongsheng Tong, Säid M Sebti, Mokenge P Malafa
• Journal: The Journal of nutritional biochemistry (J Nutr Biochem) Vol. 26 Issue 8 Pg. 797-807 (Aug 2015) ISSN: 1873-4847 [Electronic] United States
• PMID: 25997867 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• BAX protein, human
• EGR1 protein, human
• Early Growth Response Protein 1
• RNA, Small Interfering
• bcl-2-Associated X Protein
• Vitamin E
• tocotrienol, delta

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Disease Models, Animal
• Early Growth Response Protein 1 (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• In Situ Nick-End Labeling
• Oligonucleotide Array Sequence Analysis
• Pancreatic Neoplasms (genetics, metabolism)
• Promoter Regions, Genetic
• RNA, Small Interfering (genetics, metabolism)
• Signal Transduction
• Vitamin E (analogs & derivatives, pharmacology)
• bcl-2-Associated X Protein (genetics, metabolism)