title: Mitochondrial calcium uniporter silencing potentiates caspase-independent cell death in MDA-MB-231 breast cancer cells.
abstract: The mitochondrial calcium uniporter (MCU) transports free ionic Ca(2+) into the mitochondrial matrix. We assessed MCU expression in clinical breast cancer samples using microarray analysis and the consequences of MCU silencing in a breast cancer cell line. Our results indicate that estrogen receptor negative and basal-like breast cancers are characterized by elevated levels of MCU. Silencing of MCU expression in the basal-like MDA-MB-231 breast cancer cell line produced no change in proliferation or cell viability. However, distinct consequences of MCU silencing were seen on cell death pathways. Caspase-dependent cell death initiated by the Bcl-2 inhibitor ABT-263 was not altered by MCU silencing; whereas caspase-independent cell death induced by the calcium ionophore ionomycin was potentiated by MCU silencing. Measurement of cytosolic Ca(2+) levels showed that the promotion of ionomycin-induced cell death by MCU silencing occurs independently of changes in bulk cytosolic Ca(2+) levels. This study demonstrates that MCU overexpression is a feature of some breast cancers and that MCU overexpression may offer a survival advantage against some cell death pathways. MCU inhibitors may be a strategy to increase the effectiveness of therapies that act through the induction of caspase-independent cell death pathways in estrogen receptor negative and basal-like breast cancers.
authors.affiliation: School of Pharmacy, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Merril C
authors.initials: MC
authors.lastname: Curry
authors.forename: Amelia A
authors.initials: AA
authors.lastname: Peters
authors.forename: Paraic A
authors.initials: PA
authors.lastname: Kenny
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Roberts-Thomson
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Monteith
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D020868:Gene Silencing; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D015220:Calcium Channels; D012333:RNA, Messenger; D013449:Sulfonamides; C034703:mitochondrial calcium uniporter; D015759:Ionomycin; D020169:Caspases; C528561:navitoclax