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Cyclosporine A sensitizes breast cancer cells to bortezomib by inducing paraptosis
- Author(s)
- 김진
- Alternative Author(s)
- Jin Kim
- Advisor
- 최경숙
- Department
- 일반대학원 의생명과학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2020-08
- Language
- eng
- Keyword
- Ca2+; Cyclosporine A; ER stress; Paraptosis; ROS
- Alternative Abstract
- Cyclosporine A (CsA), a natural product extracted from the Tolypocladium inflatum, is known to have immunosuppressive and anti-fungal activities. In recent studies, CsA was reported to have an anti-cancer activity in breast, colon, and cervical cancer cells, but its precise underlying mechanism is not fully understood. In the present study, I found that treatment of MDA-MB 435S cells with CsA induces cytoplasmic vacuolation originated mainly from mitochondria and partially from the endoplasmic reticulum (ER), leading to growth arrest, rather than cell death. In contrast, the combination of bortezomib and CsA (Bz/CsA) accelerates cell death through the massive cytoplasmic vacuolation derived initially from mitochondria and subsequently from the ER in these cells. Bz/CsA-induced cell death as well as dilation of both mitochondria and the ER was significantly inhibited by cycloheximide, but not by the inhibitors of apoptosis, necroptosis, or autophagy, suggesting that Bz/CsA induced paraptotic cell death. I found that CsA dramatically enhances Bz-mediated ER stress. In addition, Bz/CsA triggered mitochondrial Ca2+ overload, and RU360, a specific inhibitor of mitochondrial calcium uniporter (MCU), effectively inhibited the cytoplasmic vacuolation and subsequent cell death by Bz/CsA. Furthermore, I found that reactive oxygen species (ROS) were generated in the process of mitochondria- and ER-derived vacuolation and pretreatment with antioxidants significantly attenuated Bz/CsA-induced cell death. Collectively, these results suggest that mitochondrial Ca2+ overload, enhanced ER stress, and ROS are responsible for the induction of Bz/CsA-induced paraptosis in breast cancer cells.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Biomedical Sciences > 3. Theses(Master)
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