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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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


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