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악성 유방암 세포에서 CDDO-ME 처리 시 Ca2+ 유입에 매개된 소포체 팽창과 c-FLIP 감소를 통한 세포자살 유도
- Author(s)
- 정수아
- Advisor
- 최경숙
- Department
- 일반대학원 의생명과학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2015-02
- Language
- eng
- Alternative Abstract
- Oleanolic acid-derived synthetic triterpenoids are a promising new class of compounds with antitumorigenic activity against various types of cancer cells. In this study, we show that methyl-2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oate (CDDO-ME) triggered paraptosis-like cellular vacuolation, which was mainly derived from the dilation of the endoplasmic reticulum, but finally killed breast cancer cells via apoptosis. We found that the increase in intracellular Ca2+ levels preceded CDDO-ME-induced vacuolation and cell death. In addition, this increase was accompanied by the increase in reactive oxygen species (ROS) levels. Pretreatment with Ca2+ chelator, BAPTA, BAPTA-AM or antioxidant, N-acetylcysteine effectively blocked CDDO-ME-induced vacuolation and cell death, suggesting that Ca2+ influx and ROS generation are initial critical signals for CDDO-ME-induced anti-cancer effect. Moreover, CDDO-ME markedly reduced the protein levels of c-FLIPL. Overexpression of c-FLIPL did not affect CDDO-ME-induced vacuolation, but significantly attenuated CDDO-ME-induced cell death. Interestingly, CDDO-ME increased intracellular Ca2+ and ROS levels at much lower doses, compared to CDDO and CDDO rather increased the protein levels of c-FLIPL via its proteasome inhibitory activity. Taken together, our results clearly show that both intracellular Ca2+ influx, ROS generation and c-FLIP downregulation critically contribute to the potent anti-cancer effect of CDDO-ME in breast cancer cells.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Biomedical Sciences > 3. Theses(Master)
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