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

• Published in: Apoptosis (London) 2009-11, Vol.14 (11), p.1366
• Main Authors: Wali, Vikram B, Bachawal, Sunitha V, Sylvester, Paul W
• Format: Article
• Language: English
• Subjects: Combined treatment
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1007/s10495-009-0406-y

γ-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 γ-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 γ-tocotrienol-induced apoptosis in +SA mammary tumor cells. Treatment with 15-40 μM γ-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/eIF2α/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 γ-tocotrienol-induced PARP-cleavage, CHOP and TRB3 expression. γ-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 γ-tocotrienol treatment, but combined treatment with mevalonate did not reverse γ-tocotrienol-induced apoptosis, suggesting that a decrease in HMGCoA reductase activity is not required for γ-tocotrienol induced apoptosis. These results demonstrate that ER stress apoptotic signaling is associated with γ-tocotrienol-induced apoptosis in +SA mammary tumor cells.