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

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Abstract

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.

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Acknowledgments

This work was performed at the College of Pharmacy, University of Louisiana at Monroe, Monroe, LA and supported in part by grants from the National Institutes of Health (Grant CA 86833) and First Tech International Ltd.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. College of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe, LA, 71209, USA

    Vikram B. Wali, Sunitha V. Bachawal & Paul W. Sylvester

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  1. Vikram B. Wali
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  2. Sunitha V. Bachawal
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  3. Paul W. Sylvester
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Correspondence to Paul W. Sylvester.

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Wali, V.B., Bachawal, S.V. & Sylvester, P.W. Endoplasmic reticulum stress mediates γ-tocotrienol-induced apoptosis in mammary tumor cells. Apoptosis 14, 1366–1377 (2009). https://doi.org/10.1007/s10495-009-0406-y

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