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Role of Sirt3 in regulating α-tocopheryl succinate-induced apoptosisтезисы доклада Тезисы
- Авторы: Yapryntseva M.A., Vinogradov M.A., Zhivotovsky B., Gogvadze V.
- Сборник: 31st ECDO conference "Classic meets modern: functional specificity and crosstalk of new and old types of cell death"
- Тезисы
- Год издания: 2025
- Место издания: Berlin
- Первая страница: 117
- Последняя страница: 117
- Номер статьи: 73
- Аннотация: Cancer remains one of the leading causes of mortality worldwide. A promising strategy to combat cancer involves inducing programmed cell death, including its most studied form - apoptosis. However, conventional cytotoxic chemotherapeutic drugs often exhibit limited efficacy and substantial toxicity to healthy tissues. α-tocopheryl succinate (α-TOS) has emerged as a promising anticancer agent due to its selective targeting of tumor cells. It inhibits mitochondrial respiratory complex II, leading to electron leakage, the generation of reactive oxygen species (ROS), oxidative stress, and ultimately, cell death. A key advantage of α-TOS is its tumor-selective toxicity: normal cells efficiently hydrolyze α-TOS into non-toxic vitamin E and succinate due to high esterase activity. Given that α-TOS exerts its effects directly on mitochondria, mitochondrial proteins are likely involved in regulating its cytotoxic action.Sirtuin 3 (Sirt3), a mitochondrial matrix deacetylase, is one of the crucial regulators of mitochondrial function. It modulates multiple targets, including enzymes involved in energy metabolism, antioxidant defense, and mitochondrial biogenesis. Our findings indicate that in cancer cell lines of various origins (lung and ovarian cancers, and neuroblastoma), the level of Sirt3 correlates with resistance to α-TOS. Specifically, cell lines expressing higher levels of Sirt3 (A549, A2780, and SH-SY5Y) exhibited lower levels of α-TOS-induced apoptosis compared to those with lower Sirt3 expression (U1810, ovcar8, SK-N-BE(2)).Interestingly, in addition to apoptosis, assessed by caspase-3 activation and PARP cleavage, and antioxidant response, assessed by NRF2 and GPX4 accumulation, α-TOS treatment in lung cancer cells caused accumulation and phosphorylation of the mitochondrial fission protein Drp1, alterations in cytoskeletal protein α-tubulin, inhibition of autophagy, and downregulation of Sirt3. Overexpression of Sirt3 in cell lines with low basal expression (U1810, ovcar8) suppressed α-TOS-induced apoptosis.Notably, A549 cells, which exhibit the highest Sirt3 expression, did not undergo apoptosis even at high α-TOS concentrations (200 µM). Nevertheless, clonogenic assay showed a reduced number of viable colonies following treatment, suggesting an antiproliferative rather than pro-apoptotic effect of α-TOS in these cells. Importantly, Sirt3 knockdown enhanced α-TOS efficacy in A549 cells.In conclusion, α-TOS induces mitochondrial and cytoskeletal remodeling and apoptosis in cancer cells. The intensity of apoptosis correlates inversely with Sirt3 levels—higher Sirt3 expression protects cancer cells from α-TOS-induced cell death. Therefore, modulating Sirt3 expression may represent an effective strategy to enhance tumor sensitivity to α-TOS treatment.
- Добавил в систему: Япрынцева Мария Александровна