title: 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.affiliation: Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea.|Graduate Program of Cancer Biology, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Soo Ah
authors.initials: SA
authors.lastname: Jeong
authors.affiliation: Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea.|Graduate Program of Cancer Biology, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea.
authors.forename: In Young
authors.initials: IY
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea.|Graduate Program of Cancer Biology, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea.
authors.forename: A Reum
authors.initials: AR
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea.|Graduate Program of Cancer Biology, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Mi Jin
authors.initials: MJ
authors.lastname: Yoon
authors.affiliation: Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea.|Graduate Program of Cancer Biology, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Hyeseong
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Life Science, Ajou University, Suwon, Korea.
authors.forename: Jong-Soo
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea.|Graduate Program of Cancer Biology, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Kyeong Sook
authors.initials: KS
authors.lastname: Choi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D017382:Reactive Oxygen Species; D013481:Superoxides / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D017382:Reactive Oxygen Species; D013481:Superoxides; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D002118:Calcium
keywords: CDDO-Me; Ca2+; apoptosis; c-FLIPL; endoplasmic reticulum