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Simultaneous mitochondrial Ca2+ overload and proteasomal inhibition are responsible for the induction of paraptosis in malignant breast cancer cells

Yoon, Mi Jin; Kim, Eun Hee; Kwon, Taeg Kyu; Park, Sun Ah; Choi, Kyeong Sook
Institute for Medical Sciences
We recently showed that curcumin selectively kills malignant breast cancer cells via induction of paraptosis, a mode of cell death that is accompanied by dilation of mitochondria and the endoplasmic reticulum (ER). Since mitochondria and the ER are major reservoirs of intracellular Ca2+, we herein investigated the possible involvement of Ca2+ in curcumin-induced paraptosis. We found that curcumin markedly increased mitochondrial Ca2+ levels in the MDA-MB 435S and MDA-MB 231 breast cancer cell lines, but not in the MCF-10A normal breast cell lines. Pretreatment with the uniporter inhibitors, ruthenium red or Ru360, effectively inhibited the curcumin-induced dilation of both mitochondria and the ER, and blocked cell death. Furthermore, curcumin-induced paraptotic signals, including increases in mitochondrial superoxide levels, activation of ERKs and downregulation of Alix, were blocked by ruthenium pretreatment. Curcumin-induced proteasomal dysfunction and CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) induction were also considerably attenuated by ruthenium pretreatment, suggesting that mitochondrial Ca2+ influxes may act as crucial early signals for curcumin-induced paraptosis. Interestingly, combined treatment with the mitochondrial Na+/Ca2+ exchanger (mNCX; CGP-37157 or diltiazem) and a proteasome inhibitor (bortezomib, MG132 or lactacystin) effectively induced paraptotic cell death, whereas treatment with either agent alone did not. Taken together, our results show that simultaneous mitochondrial Ca2+ overload and proteasomal inhibition are required for the effective induction of paraptosis in breast cancer cells. Furthermore, our results suggest that the resistance of malignant breast cancer cells to proteasomal inhibitors might be effectively overcome by triggering an mNCX-mediated mitochondrial Ca2+ overload, leading to the induction of paraptosis.
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