MCU-i4,a mitochondrial Ca^(2+)uniporter modulator,induces breast cancer BT474 cell death by enhancing glycolysis,ATP production and reactive oxygen species(ROS)burst  

作　　者：EDMUND CHEUNG SO LOUIS W.C.CHOW CHIN-MIN CHUANG CING YU CHEN CHENG-HSUN WU LIAN-RU SHIAO TING-TSZ OU KAR-LOK WONG YUK-MAN LEUNG YI-PING HUANG 

机构地区：[1]Department of Anesthesia,An Nan Hospital,China Medical University,Tainan,709,Taiwan,China [2]Graduate Institute of Medical Sciences,Chang Jung Christian University,Tainan,711301,Taiwan,China [3]UNIMED Medical Institute,Hong Kong SAR,China [4]Department of Emergency Medicine,China Medical University Hospital,Taichung,404327,Taiwan,China [5]Department of Cosmetic Science,Providence University,Taichung,43301,Taiwan,China [6]School of Pharmacy,China Medical University,Taichung,404328,Taiwan,China [7]Department of Anatomy,China Medical University,Taichung,404328,Taiwan,China [8]Department of Physiology,China Medical University,Taichung,404328,Taiwan,China [9]Department of Medicinal Botanicals and Healthcare,Dayeh University,Changhua,51591,Taiwan,China [10]Department of Anesthesiology,Kuang Tien General Hospital,Shalu,Taichung,433,Taiwan,China

出　　处：《Oncology Research》2025年第2期397-406,共10页肿瘤学研究(英文)

基　　金：China Medical University and China Medical University Hospital,Taiwan for providing fundings(CMU111-S-20,CMU112-S-59,DMR-112-067);ECS thanks An Nan Hospital for support(ANHRF112-04).

摘　　要：Objectives:Mitochondrial Ca^(2+)uniporter(MCU)provides a Ca^(2+)influx pathway from the cytosol into the mitochondrial matrix and a moderate mitochondrial Ca^(2+)rise stimulates ATP production and cell growth.MCU is highly expressed in various cancer cells including breast cancer cells,thereby increasing the capacity of mitochondrial Ca^(2+)uptake,ATP production,and cancer cell proliferation.The objective of this study was to examine MCU inhibition as an anti-cancer mechanism.Methods:The effects of MCU-i4,a newly developed MCU inhibitor,on cell viability,apoptosis,cytosolic Ca^(2+),mitochondrial Ca^(2+)and potential,glycolytic rate,generation of ATP,and reactive oxygen species,were examined in breast cancer BT474 cells.Results:MCU-i4 caused apoptotic cell death,and it decreased and increased,respectively,mitochondrial and cytosolic Ca^(2+)concentration.Inhibition of MCU by MCU-i4 revealed that cytosolic Ca^(2+)elevation resulted from endoplasmic reticulum(ER)Ca^(2+)release via inositol 1,4,5-trisphosphate receptors(IP3R)and ryanodine receptors(RYR).Unexpectedly,MCU-i4 enhanced glycolysis and ATP production;it also triggered a large production of reactive oxygen species(ROS)and mitochondrial membrane potential collapse.Conclusion:Cytotoxic mechanisms of MCU-i4 in cancer cells involved enhanced glycolysis and heightened formation of ATP and ROS.It is conventionally believed that cancer cell death could be caused by inhibition of glycolysis.Our observations suggest cancer cell death could also be induced by increased glycolytic metabolism.

关 键 词：BT474 cells Breast cancer MCU-i4 Cell death Mitochondria Ca^(2+)uniporter(MCU) 

分 类 号：R737.9[医药卫生—肿瘤]