Ca2+ influx-mediated dilation of the endoplasmic reticulum and c-FLIPL downregulation trigger CDDO-Me-induced apoptosis in breast cancer cells
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Soo Ah Jeong1,2,*, In Young Kim1,2,*, A Reum Lee1,2, Mi Jin Yoon1,2, Hyeseong Cho1,2, Jong-Soo Lee3, Kyeong Sook Choi1,2
1Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea
2Graduate Program of Cancer Biology, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea
3Department of Life Science, Ajou University, Suwon, Korea
*These authors have contributed equally to this work
Kyeong Sook Choi, e-mail: [email protected]
Keywords: CDDO-Me, endoplasmic reticulum, Ca2+, c-FLIPL, apoptosis
Received: January 23, 2015 Accepted: May 12, 2015 Published: May 25, 2015
The synthetic triterpenoid 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-C28-methyl ester (CDDO-Me) is considered a promising anti-tumorigenic compound. In this study, we show that treatment with CDDO-Me induces progressive endoplasmic reticulum (ER)-derived vacuolation in various breast cancer cells and ultimately kills these cells by inducing apoptosis. We found that CDDO-Me–induced increases in intracellular Ca2+ levels, reflecting influx from the extracellular milieu, make a critical contribution to ER-derived vacuolation and subsequent cell death. In parallel with increasing Ca2+ levels, CDDO-Me markedly increased the generation of reactive oxygen species (ROS). Interestingly, there exists a reciprocal positive-regulatory loop between Ca2+ influx and ROS generation that triggers ER stress and ER dilation in response to CDDO-Me. In addition, CDDO-Me rapidly reduced the protein levels of c-FLIPL (cellular FLICE-inhibitory protein) and overexpression of c-FLIPL blocked CDDO-Me–induced cell death, but not vacuolation. These results suggest that c-FLIPL downregulation is a key contributor to CDDO-Me–induced apoptotic cell death, independent of ER-derived vacuolation. Taken together, our results show that ER-derived vacuolation via Ca2+ influx and ROS generation as well as caspase activation via c-FLIPL downregulation are responsible for the potent anticancer effects of CDDO-Me on breast cancer cells.
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