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Tocotrienols induce apoptosis in breast cancer cell lines via an endoplasmic reticulum stress-dependent increase in extrinsic death receptor signaling

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Abstract

Tocotrienols are naturally occurring forms of vitamin E based on their structural similarity. This study focused on investigating anticancer effects of tocotrienols and the mechanisms of apoptosis induction by tocotrienols in vivo and in vitro. Dietary delivery of γ-tocotrienol (γ-T3) suppressed tumor growth in a syngeneic implantation mouse mammary cancer model by inhibiting cell proliferation and inducing apoptosis. In cell culture studies, γ-T3 inhibited colony formation of a mouse mammary cancer cell line and human breast cancer cell lines. The anti-proliferative effects of tocotrienols were highly correlated with an increase in apoptosis based on Annexin V assessment. Treatment of human MDA-MB-231 and MCF-7 cells with γ-T3 induced cleavages of PARP as well as caspase-8, -9, and -3. Additional analyses showed that γ-T3 activated c-Jun NH2-terminal kinase (JNK) and p38 MAPK, and upregulated death receptor 5 (DR5) and C/EBP homologous protein (CHOP), an endoplasmic reticulum (ER) stress marker. Silencing either JNK or p38 MAPK reduced the increase in DR5 and CHOP and partially blocked γ-T3-induced apoptosis. Both DR5 and CHOP upregulation were required for γ-T3-induced apoptosis, and DR5 was transcriptionally regulated by CHOP after γ-T3 treatment. Moreover, γ-T3 increased the level of other ER-stress markers. Taken together, these results suggest that upregulation of DR5 by γ-T3 treatment is dependent on JNK and p38 MAPK activation which is mediated by ER-stress.

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Acknowledgments

This research was supported by the Clayton Foundation for Research and the National Institute of Environmental Health Sciences Center Grant ES007784.

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Authors and Affiliations

  1. Institute of Cellular and Molecular Biology/A5000, The University of Texas at Austin, Austin, TX, 78712, USA

    Sook Kyung Park

  2. Section of Molecular Genetics and Microbiology/School of Biological Sciences/C0900, The University of Texas at Austin, Austin, TX, 78712, USA

    Bob G. Sanders

  3. Department of Nutritional Sciences/A2703, The University of Texas at Austin, Austin, TX, 78712, USA

    Kimberly Kline

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  1. Sook Kyung Park
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Correspondence to Kimberly Kline.

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Park, S.K., Sanders, B.G. & Kline, K. Tocotrienols induce apoptosis in breast cancer cell lines via an endoplasmic reticulum stress-dependent increase in extrinsic death receptor signaling. Breast Cancer Res Treat 124, 361–375 (2010). https://doi.org/10.1007/s10549-010-0786-2

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