| ○種別 (必須): | □ | 学術論文 (審査論文)
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| ○言語 (必須): | □ | 英語
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| ○審査 (推奨): | □ | Peer Review
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| ○著者 (必須): | 1. | (英) Manobendro Nath Ray (日) Ray Manobendro Nath (読) れい まのべんどろ なす
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| ○学籍番号 (推奨): | □ | ****
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| 2. | 大園 瑞音
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| 3. | 中尾 允泰 ([徳島大学.大学院医歯薬学研究部.薬学域.薬科学部門.創薬科学系.分子創薬化学])
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| 4. | 佐野 茂樹 ([徳島大学.大学院医歯薬学研究部.薬学域.薬科学部門.創薬科学系.分子創薬化学])
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| 5. | 小暮 健太朗 ([徳島大学.大学院医歯薬学研究部.薬学域.薬科学部門.創薬科学系.衛生薬学])
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| ○題名 (必須): | □ | (英) Only one carbon difference determines the pro-apoptotic activity of α-tocopheryl esters (日)
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| ○副題 (任意): |
| ○要約 (任意): | □ | (英) α-Tocopheryl succinate (TS), a redox-silent succinyl ester of natural α-Tocopherol, has emerged as a novel anti-cancer 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 Ca in cultured cells, suggesting induction of endoplasmic reticulum (ER) stress; however, Tglu did not affect Ca homeostasis. 1,4,5-trisphosphate (IP ) receptor antagonist 2-Aminoethyl diphenylborinate (2-APB) decreased TS-induced intracellular Ca , 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 Ca 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. (日)
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| ○キーワード (推奨): |
| ○発行所 (推奨): |
| ○誌名 (必須): | □ | The FEBS Journal ([Federation of European Biochemical Societies])
(pISSN: 1742-464X, eISSN: 1742-4658)
| ○ISSN (任意): | □ | 1742-4658
ISSN: 1742-464X
(pISSN: 1742-464X, eISSN: 1742-4658) Title: The FEBS journalTitle(ISO): FEBS JSupplier: Federation of European Biochemical SocietiesPublisher: Wiley Publishing (NLM Catalog)
(Wiley)
(Scopus)
(CrossRef)
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| ○巻 (必須): | □ | 290
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| ○号 (必須): | □ |
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| ○頁 (必須): | □ | 1027 1048
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| ○都市 (任意): |
| ○年月日 (必須): | □ | 西暦 2023年 2月 初日 (令和 5年 2月 初日)
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| ○URL (任意): |
| ○DOI (任意): | □ | 10.1111/febs.16623 (→Scopusで検索)
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| ○PMID (任意): | □ | 36083714 (→Scopusで検索)
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| ○Scopus (任意): | □ | 2-s2.0-85138289941
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| ○評価値 (任意): |
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| ○指導教員 (推奨): | 1. | 小暮 健太朗 ([徳島大学.大学院医歯薬学研究部.薬学域.薬科学部門.創薬科学系.衛生薬学])
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| ○備考 (任意): | 1. | (英) Article.ELocationID: 10.1111/febs.16623 (日)
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| 2. | (英) Article.PublicationTypeList.PublicationType: Journal Article (日)
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| 3. | (英) KeywordList.Keyword: GRP78 (日)
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| 4. | (英) KeywordList.Keyword: apoptosis (日)
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| 5. | (英) KeywordList.Keyword: endoplasmic reticulum stress (日)
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| 6. | (英) KeywordList.Keyword: structure-activity relationship (日)
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| 7. | (英) KeywordList.Keyword: α-tocopheryl ester (日)
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