Only one carbon difference determines the pro‐apoptotic activity of α‐tocopheryl esters. (19th September 2022)

• Record Type: Journal Article
• Authors: Ray, Manobendro Nath; Ozono, Mizune; Nakao, Michiyasu; Sano, Shigeki; Kogure, Kentaro
• Is Part Of: FEBS journal. Volume 290:Number 4(2023)
• Page Start: 1027
• Page End: 1048
• Publication Date: 2022-09-19
• Subjects: apoptosis -- endoplasmic reticulum stress -- GRP78 -- structure–activity relationship -- α‐tocopheryl ester; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.16623
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : 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 2+ in cultured cells, suggesting induction of endoplasmic reticulum (ER) stress; however, Tglu did not affect Ca 2+ homeostasis. 1, 4, 5‐trisphosphate (IP3 ) receptor antagonist 2‐Aminoethyl diphenylborinate (2‐APB) decreased TS‐induced intracellular Ca 2+, 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 2+ 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. Abstract : Tocopheryl succinate (TS) and Tocopheryl glutaate (Tglu) are the esters of α‐Tocopherol. TS consists of four carbon atoms in the terminal di‐carboxylic moiety, while Tglu consists of five carbon atoms. Interestingly, structural difference by only one carbon oppositely affects biological activities, which explains the opposite role of TS and Tglu in apoptosis induction. We propose that tocopheryl esters are versatile in biological activities that can be explored in the future.