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ID 117788
タイトル別表記
Mechanism of apoptosis induction by tocopheryl esters
著者
Ray, Manobendro Nath Tokushima University
キーワード
α-Tocopheryl ester
Structure-activity relationship
Endoplasmic reticulum stress
GRP78
Apoptosis
資料タイプ
学術雑誌論文
抄録
α-Tocopheryl succinate (TS), a redox-silent succinyl ester of natural α-Tocopherol, has emerged as a novel anticancer agent. However, the underlying mechanism is unclear. We found that the terminal dicarboxylic moiety of tocopheryl esters contributes to apoptosis induction and thus cytotoxicity. To further examine this relationship, we compared the pro-apoptotic activity of TS, which has four carbon atoms in the terminal dicarboxylic moiety, to that of a newly synthesized, tocopheryl glutarate (Tglu), which has five. Cytotoxicity assays in vitro confirmed that TS stimulated apoptosis, while Tglu was non-cytotoxic. In investigating biological mechanisms leading to these opposing effects, we found that TS caused an elevation of intracellular superoxide, but Tglu did not. TS increased intracellular Ca2+ in cultured cells, suggesting induction of endoplasmic reticulum (ER) stress; however, Tglu did not affect Ca2+ homeostasis. 1,4,5-trisphosphate (IP3) receptor antagonist 2-Aminoethyl diphenylborinate (2-APB) decreased TS-induced intracellular Ca2+, restored mitochondrial activity and cell viability in TS-treated cells, establishing the ER-mitochondria relationship in apoptosis induction. Moreover, real-time PCR, immunostaining and Western blotting assays revealed that TS downregulated glucose-regulated protein 78 (GRP78), which maintains ER homeostasis and promotes cell survival. Conversely, Tglu upregulates GRP78. Taken together, our results suggest a model in which TS-mediated superoxide production and GRP78 inhibition induce ER stress, which elevates intracellular Ca2+ and depolarizes mitochondria, leading to apoptosis. Because Tglu does not affect superoxide generation and increases GRP78 expression, it inhibits ER stress and is thereby non-cytotoxic. Our research provides insight into the structure-activity relationship of tocopheryl esters regarding the induction of apoptosis.
掲載誌名
The FEBS Journal
ISSN
17424658
1742464X
cat書誌ID
AA11998513
AA12092067
出版者
Federation of European Biochemical Societies|Wiley
発行日
2022-09-09
備考
論文本文は2023-09-19以降公開予定
権利情報
This is the peer reviewed version of the following article: Ray, M.N., Ozono, M., Nakao, M., Sano, S. and Kogure, K. (2022), Only one carbon difference determines the pro-apoptotic activity of α-tocopheryl esters. FEBS J., which has been published in final form at https://doi.org/10.1111/febs.16623. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.
EDB ID
出版社版DOI
出版社版URL
言語
eng
著者版フラグ
その他
部局
薬学系