Only one carbon difference determines the pro-apoptotic activity of α-tocopheryl esters
Manobendro Nath Ray1, Mizune Ozono2, Michiyasu Nakao3
1Department of Pharmaceutical Health Chemistry, Graduate School of Pharmaceutical Sciences, Tokushima University, Japan.
The FEBS Journal
|September 9, 2022
Summary
α-Tocopheryl succinate (TS) induces cancer cell death by increasing superoxide and ER stress, while tocopheryl glutarate (Tglu) does not. This research clarifies the structure-activity relationship of tocopheryl esters in apoptosis induction.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- α-Tocopheryl succinate (TS) is a novel anti-cancer agent, but its mechanism of action is not fully understood.
- The terminal dicarboxylic moiety of tocopheryl esters is implicated in apoptosis induction and cytotoxicity.
- Understanding the structure-activity relationship is crucial for developing effective cancer therapies.
Purpose of the Study:
- To investigate the mechanism by which α-tocopheryl succinate (TS) induces apoptosis.
- To compare the pro-apoptotic activity of TS with a newly synthesized tocopheryl glutarate (Tglu).
- To elucidate the role of endoplasmic reticulum (ER) stress and mitochondrial function in TS-induced cytotoxicity.
Main Methods:
- In vitro cytotoxicity assays comparing TS and Tglu.
- Measurement of intracellular superoxide and calcium (Ca2+) levels.
- Utilized 1,4,5-trisphosphate (IP3) receptor antagonist (2-APB) to probe ER-mitochondria signaling.
- Real-time PCR, immunostaining, and Western blotting to assess GRP78 expression.
- Investigated the impact on mitochondrial activity and cell viability.
Main Results:
- TS demonstrated significant cytotoxicity and induced apoptosis, whereas Tglu was non-cytotoxic.
- TS elevated intracellular superoxide and Ca2+, indicating ER stress, while Tglu did not.
- 2-APB treatment partially restored mitochondrial activity and cell viability in TS-treated cells.
- TS downregulated glucose-regulated protein 78 (GRP78), a key regulator of ER homeostasis, while Tglu upregulated it.
Conclusions:
- TS-mediated superoxide production and GRP78 inhibition induce ER stress, leading to elevated intracellular Ca2+, mitochondrial depolarization, and apoptosis.
- Tglu's inability to affect superoxide generation and its GRP78 upregulation inhibit ER stress, rendering it non-cytotoxic.
- This study establishes a clear structure-activity relationship for tocopheryl esters in apoptosis induction, highlighting the role of ER-mitochondria crosstalk.
