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J Nutr Biochem. 2015 Aug;26(8):797-807. doi: 10.1016/j.jnutbio.2015.02.008. Epub 2015 Apr 1.

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

Author information

1
Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL; Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
2
Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL.
3
Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL; Department of School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China.
4
Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL.
5
Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL.
6
Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
7
Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL.
8
Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL; Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL. Electronic address: mokenge.malafa@moffitt.org.

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.

KEYWORDS:

Apoptosis; Early gene; Early growth response protein 1; Pancreatic cancer; Vitamin E; δ-Tocotrienol

PMID:
25997867
PMCID:
PMC4576995
DOI:
10.1016/j.jnutbio.2015.02.008
[Indexed for MEDLINE]
Free PMC Article

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