Ca2+ influx-mediated dilation of the endoplasmic reticulum and c-FLIPL downregulation trigger CDDO-Me-induced apoptosis in breast cancer cells.

Abstract

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.

• Authors: Soo Ah Jeong, In Young Kim, A Reum Lee, Mi Jin Yoon, Hyeseong Cho, Jong-Soo Lee, Kyeong Sook Choi
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 25 Pg. 21173-92 (Aug 28 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26053096 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• Reactive Oxygen Species
• Superoxides
• Oleanolic Acid
• bardoxolone methyl
• Calcium

Topics

• Antineoplastic Agents (chemistry)
• Apoptosis
• Breast Neoplasms (drug therapy, metabolism, pathology)
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism)
• Calcium (metabolism)
• Cell Line, Tumor
• Cell Survival
• Cytosol (metabolism)
• Down-Regulation
• Endoplasmic Reticulum (metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Microscopy, Electron, Transmission
• Mitochondria (metabolism)
• Oleanolic Acid (analogs & derivatives, chemistry)
• Reactive Oxygen Species
• Superoxides (chemistry)