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Breast Cancer Research and Treatment

, Volume 124, Issue 2, pp 361–375 | Cite as

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

  • Sook Kyung Park
  • Bob G. Sanders
  • Kimberly Kline
Preclinical study

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.

Keywords

Tocotrienols Apoptosis Breast cancer 66cl-4 mouse mammary tumor model Endoplasmic reticulum stress Death receptor 5 C/EBP homologous protein 

Notes

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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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Sook Kyung Park
    • 1
  • Bob G. Sanders
    • 2
  • Kimberly Kline
    • 3
  1. 1.Institute of Cellular and Molecular Biology/A5000The University of Texas at AustinAustinUSA
  2. 2.Section of Molecular Genetics and Microbiology/School of Biological Sciences/C0900The University of Texas at AustinAustinUSA
  3. 3.Department of Nutritional Sciences/A2703The University of Texas at AustinAustinUSA

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