Lactate dehydrogenases amplify reactive oxygen species in cancer cells in response to oxidative stimuli  

作　　者：Hao Wu Yuqi Wang Minfeng Ying Chengmeng Jin Jiangtao Li Xun Hu 

机构地区：[1]Cancer Institute(Key Laboratory for Cancer Intervention and Prevention,China National Ministry of Education,Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences),The Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,China [2]Department of Surgery,The Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,China

出　　处：《Signal Transduction and Targeted Therapy》2021年第7期2238-2250,共13页信号转导与靶向治疗（英文）

基　　金：This work has been supported in part by the China National 973 project(2013CB911303);China Natural Sciences Foundation projects(81470126);a key project(2018C03009)funded by Zhejiang Provincial Department of Sciences and Technologies;the Fundamental Research Funds for the Central Universities(2017XZZX001-012019FZJD009);National Ministry of Education,China,to X.H.,and Zhejiang Provincial Natural Science Foundation of China(LY17H160036);the Fundamental Research Funds for the Central Universities(2017FZA7010);China Natural Sciences Foundation project(81301707),to H.W.

摘　　要：Previous studies demonstrated that superoxide could initiate and amplify LDH-catalyzed hydrogen peroxide production in aqueous phase,but its physiological relevance is unknown.Here we showed that LDHA and LDHB both exhibited hydrogen peroxide-producing activity,which was significantly enhanced by the superoxide generated from the isolated mitochondria from HeLa cells and patients'cholangiocarcinoma specimen.After LDHA or LDHB were knocked out,hydrogen peroxide produced by Hela or 4T1 cancer cells were significantly reduced.Re-expression of LDHA in LDHA-knockout HeLa cells partially restored hydrogen peroxide production.In HeLa and 4T1 cells,LDHA or LDHB knockout or LDH inhibitor FX11 significantly decreased ROS induction by modulators of the mitochondrial electron transfer chain(antimycin,oligomycin,rotenone),hypoxia,and pharmacological ROS inducers piperlogumine(PL)and phenethyl isothiocyanate(PEITC).Moreover,the tumors formed by LDHA or LDHB knockout HeLa or 4T1 cells exhibited a significantly less oxidative state than those formed by control cells.Collectively,we provide a mechanistic understanding of a link between LDH and cellular hydrogen peroxide production or oxidative stress in cancer cells in vitro and in vivo.

关 键 词：amplify CANCER OXIDATIVE 

分 类 号：R730[医药卫生—肿瘤]