Endoplasmic reticulum stress mediates gamma-tocotrienol-induced apoptosis in mammary tumor cells.

Abstract

gamma-Tocotrienol, a member of the vitamin E family of compounds, induces apoptosis in a variety of cancer cell types. However, previous studies have clearly demonstrated that gamma-tocotrienol-induced apoptosis in neoplastic mouse +SA mammary epithelial cells is not mediated through mitochondrial stress or death receptor apoptotic signaling. Therefore, studies were conducted to determine the role of endoplasmic reticulum (ER) stress in mediating gamma-tocotrienol-induced apoptosis in +SA mammary tumor cells. Treatment with 15-40 microM gamma-tocotrienol induced +SA cell death in a dose-responsive manner, and these effects were associated with a corresponding increase in poly (ADP-ribose) polymerase (PARP)-cleavage and activation of protein kinase-like endoplasmic reticulum kinase/eukaryotic translational initiation factor/activating transcription factor 4 (PERK/eIF2alpha/ATF-4) pathway, a marker of ER stress response. These treatments also caused a large increase in C/EBP homologous protein (CHOP) levels, a key component of ER stress mediated apoptosis that increases expression of tribbles 3 (TRB3). Knockdown of CHOP by specific siRNAs attenuated gamma-tocotrienol-induced PARP-cleavage, CHOP and TRB3 expression. gamma-Tocotrienol treatment also reduced full-length caspase-12 levels, an indication of caspase-12 cleavage and activation. Intracellular levels of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase, an ER-transmembrane enzyme catalyzing the synthesis of mevalonate, decreased following gamma-tocotrienol treatment, but combined treatment with mevalonate did not reverse gamma-tocotrienol-induced apoptosis, suggesting that a decrease in HMGCoA reductase activity is not required for gamma-tocotrienol induced apoptosis. These results demonstrate that ER stress apoptotic signaling is associated with gamma-tocotrienol-induced apoptosis in +SA mammary tumor cells.

• Authors: Vikram B Wali, Sunitha V Bachawal, Paul W Sylvester
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 14 Issue 11 Pg. 1366-77 (Nov 2009) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 19771520 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• Chromans
• Ddit3 protein, mouse
• TRB3 protein, mouse
• Vitamin E
• Transcription Factor CHOP
• plastochromanol 8
• Hydroxymethylglutaryl CoA Reductases
• Poly(ADP-ribose) Polymerases
• Casp12 protein, mouse
• Caspase 12

Topics

• Animals
• Apoptosis (drug effects)
• Caspase 12 (metabolism)
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chromans (pharmacology)
• Dose-Response Relationship, Drug
• Endoplasmic Reticulum (pathology)
• Hydroxymethylglutaryl CoA Reductases (metabolism)
• Mammary Neoplasms, Animal (pathology)
• Mice
• Poly(ADP-ribose) Polymerases (metabolism)
• Signal Transduction (drug effects)
• Transcription Factor CHOP (metabolism)
• Vitamin E (analogs & derivatives, pharmacology)