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악성 유방암 세포에서 paraptosis 유도 기전 연구
- Author(s)
- 윤미진
- Advisor
- 최경숙
- Department
- 일반대학원 분자과학기술학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2012-08
- Language
- eng
- Keyword
- Malignant breast cancer cells; Paraptosis; Mitochondrial Ca2+; Superoxide; Proteasome inhibition
- Alternative Abstract
- Defects in apoptotic signaling pathways contribute to the development of cancer and to therapy resistance (e.g. chemo- and radiotherapy) in many types of malignant tumors. Therefore, there is an urgent need to elucidate the molecular basis of apoptosis resistance and to develop novel strategies to overcome this resistance. Here, we show for the first time that curcumin effectively induces paraptosis in malignant breast cancer cell lines by promoting vacuolation that results from swelling and fusion of mitochondria and/or the endoplasmic reticulum (ER). In this study, we investigated the role of mitochondrial superoxide and Ca2+ in curcumin-induced paraptosis. Curcumin induced mitochondrial Ca2+ overload and increased superoxide levels selectively in the malignant breast cancer cells, but not in the normal breast cell, contributing to the dilation of mitochondria/ER and subsequent paraptotic cell death. Combined treatment with the mitochondrial Na+/ Ca2+ exchanger inhibitor (mNCX; CGP-37157 or diltiazem) and a proteasome inhibitor (bortezomib, MG132 or lactacystin) effectively induced paraptotic cell death in MDA-MB 435S cells, whereas treatment with either agent alone did not. Thus, for effective induction of paraptosis in malignant breast cancer cells, simultaneous mitochondrial Ca2+ overload, mitochondrial superoxide generation and proteasomal inhibition are required. However, although curcumin exhibits growth-suppressive activity against a variety of cancer cells, its poor absorption and low systemic bioavailability of curcumin limit its translation into clinics as an anti-cancer agent. In this study, we show that dimethoxycurcumin (DMC), a methylated analogue of curcumin with improved stability, is significantly more potent than curcumin both in vitro and in vivo, while both DMC and curcumin were not cytotoxic to normal breast cells. DMC induced more effectively induced paraptosis, the cell death mode which is accompanied by dilation of mitochondria and the ER, than curcumin via stronger inhibition of proteasome and higher induction of CHOP. These results indicate that DMC exerts more potent anti-cancer effect on malignant breast cancer cells than curcumin through induction of paraptosis by stronger inhibition of proteasome activity.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Molecular Science and Technology > 3. Theses(Master)
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