Glycolytic potential enhanced by blockade of pyruvate influx into mitochondria sensitizes prostate cancer to detection and radiotherapy  

作　　者：Huan Xu Junyi Chen Zhi Cao Xi Chen Caihong Huang Jin Ji Yalong Xu Junfeng Jiang Yue Wang Guowang Xu Lina Zhou Jingyi He Xuedong Wei Jason Boyang Wu Zhong Wang Shancheng Ren Fubo Wang 

机构地区：[1]Department of Urology,Shanghai Changhai Hospital,Second Military Medical University,Shanghai 200433,China [2]Department of Urology,Shanghai Ninth People’s Hospital,Shanghai 200011,China [3]Department of Urology,the Second Affiliated Hospital of Fujian Medical University,Quanzhou 362000,China [4]Department of Urology,No.971 Hospital of the People’s Liberation Army Navy,Qingdao 266000,China [5]Center for Genomic and Personalized Medicine,Guangxi Key Laboratory for Genomic and Personalized Medicine,Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine,Guangxi Medical University,Nanning 530021,China [6]Research Center of Developmental Biology,Second Military Medical University,Shanghai 200433,China [7]Dalian Institute of Chemical Physics,Chinese Academy of Sciences,Dalian 116023,China [8]Department of Urology,the First Affiliated Hospital of Soochow University,Suzhou 215006,China [9]Department of Pharmaceutical Sciences,College of Pharmacy and Pharmaceutical Sciences,Washington State University,Spokane,WA 99202,USA

出　　处：《Cancer Biology & Medicine》2022年第9期1315-1333,共19页癌症生物学与医学（英文版）

基　　金：supported by the National Natural Science Foundation of China(NSFC)(Grant No.81902616 to F.W.);Science and Technology Support Project in the field of biomedicine of Shanghai Science and Technology Action Plan(Grant No.19441909200,F.W.);Clinical Research Project of Shanghai Municipal Commission of Health and Family Planning(Grant No.20184Y0130,F.W.);Precision Medicine Program of Second Military Medical University(Grant No.2017JZ35,F.W.);Youth Startup Program of the Second Military Medical University(Grant No.2016QN12,F.W.);Jiangsu Provincial Medical Youth Talent(Grant No.QNRC2016739,X.W.);Shanghai Sailing Program(Grant No.21YF1423300,H.X.);Natural Science Foundation of Shanghai(Grant No.21ZR1437800,H.X.);Cross-disciplinary Research Fund of Shanghai Ninth People’s Hospital,Shanghai Jiaotong University School of Medicine(Grant No.YG2021QN75,H.X.).

摘　　要：Objective:This study aimed to evaluate the effects of mitochondrial pyruvate carrier(MPC)blockade on the sensitivity of detection and radiotherapy of prostate cancer(PCa).Methods:We investigated glycolysis reprogramming and MPC changes in patients with PCa by using metabolic profiling,RNASeq,and tissue microarrays.Transient blockade of pyruvate influx into mitochondria was observed in cellular studies to detect its different effects on prostate carcinoma cells and benign prostate cells.Xenograft mouse models were injected with an MPC inhibitor to evaluate the sensitivity of 18F-fluorodeoxyglucose positron emission tomography with computed tomography and radiotherapy of PCa.Furthermore,the molecular mechanism of this different effect of transient blockage towards benign prostate cells and prostate cancer cells was studied in vitro.Results:MPC was elevated in PCa tissue compared with benign prostate tissue,but decreased during cancer progression.The transient blockade increased PCa cell proliferation while decreasing benign prostate cell proliferation,thus increasing the sensitivity of PCa cells to 18F-PET/CT(SUVavg,P=0.016;SUVmax,P=0.03)and radiotherapy(P<0.01).This differential effect of MPC on PCa and benign prostate cells was dependent on regulation by a VDAC1-MPC-mitochondrial homeostasis-glycolysis pathway.Conclusions:Blockade of pyruvate influx into mitochondria increased glycolysis levels in PCa but not in non-carcinoma prostate tissue.This transient blockage sensitized PCa to both detection and radiotherapy,thus indicating that glycolytic potential is a novel mechanism underlying PCa progression.The change in the mitochondrial pyruvate influx caused by transient MPC blockade provides a critical target for PCa diagnosis and treatment.

关 键 词：Glycolytic potential prostate cancer mitochondrial pyruvate carrier(MPC) mitochondria pyruvate influx diagnosis RADIOTHERAPY 

分 类 号：R737.25[医药卫生—肿瘤]