title: Release of Ca2+ from the endoplasmic reticulum and its subsequent influx into mitochondria trigger celastrol-induced paraptosis in cancer cells.
abstract: Celastrol, a triterpene extracted from the Chinese "Thunder of God Vine", is known to have anticancer activity, but its underlying mechanism is not completely understood. In this study, we show that celastrol kills several breast and colon cancer cell lines by induction of paraptosis, a cell death mode characterized by extensive vacuolization that arises via dilation of the endoplasmic reticulum (ER) and mitochondria. Celastrol treatment markedly increased mitochondrial Ca2+ levels and induced ER stress via proteasome inhibition in these cells. Both MCU (mitochondrial Ca2+ uniporter) knockdown and pretreatment with ruthenium red, an inhibitor of MCU, inhibited celastrol-induced mitochondrial Ca2+ uptake, dilation of mitochondria/ER, accumulation of poly-ubiquitinated proteins, and cell death in MDA-MB 435S cells. Inhibition of the IP3 receptor (IP3R) with 2-aminoethoxydiphenyl borate (2-APB) also effectively blocked celastrol-induced mitochondrial Ca2+ accumulation and subsequent paraptotic events. Collectively, our results show that the IP3R-mediated release of Ca2+ from the ER and its subsequent MCU-mediatedinflux into mitochondria critically contribute to celastrol-induced paraptosis in cancer cells.
authors.affiliation: Department of Biochemistry, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon , Korea. These authors contributed equally to this work. .
authors.forename: Mi Jin
authors.initials: MJ
authors.lastname: Yoon
authors.affiliation: Department of Biochemistry, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon , Korea. These authors contributed equally to this work.
authors.forename: A Reum
authors.initials: AR
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, 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, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon , Korea.
authors.forename: You-Sun
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon , Korea. Discovery Biology Group, Institut Pasteur Korea, Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do , South Korea. .
authors.forename: Jin Yeop
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Discovery Biology Group, Institut Pasteur Korea, Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do , South Korea.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Kwon
authors.affiliation: Department of Biochemistry, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon , Korea.
authors.forename: Kyeong Sook
authors.initials: KS
authors.lastname: Choi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008928:Mitochondria / Q000378:metabolism*; D053978:Pentacyclic Triterpenes; D014162:Transfection; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C050414:celastrol; D002118:Calcium