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Breast Cancer Research and Treatment

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01.11.2010 | Preclinical study

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

verfasst von: Sook Kyung Park, Bob G. Sanders, Kimberly Kline

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 2/2010

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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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Titel: Tocotrienols induce apoptosis in breast cancer cell lines via an endoplasmic reticulum stress-dependent increase in extrinsic death receptor signaling
verfasst von: Sook Kyung Park
Bob G. Sanders
Kimberly Kline
Publikationsdatum: 01.11.2010
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 2/2010
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-010-0786-2

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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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