ADP-dependent glucokinase controls metabolic fitness in prostate cancer progression  

作　　者：Hang Xu Yi-Fan Li Xian-Yan-Ling Yi Xiao-Nan Zheng Yang Yang Yan Wang Da-Zhou Liao Jia-Peng Zhang Ping Tan Xing-Yu Xiong Xi Jin Li-Na Gong Shi Qiu De-Hong Cao Hong Li Qiang Wei Lu Yang Jian-Zhong Ai 

机构地区：[1]Department of Urology,West China Hospital,Sichuan University,Chengdu,610041,China [2]Institute of Urology,West China Hospital,Sichuan University,Chengdu,610041,China [3]Animal Experimental Center,West China Hospital,Sichuan University,Chengdu,610041,China [4]Research Core Facility,West China Hospital,Sichuan University,Chengdu,610041,China

出　　处：《Military Medical Research》2024年第5期643-662,共20页军事医学研究（英文版）

基　　金：National Key R&D Plan(2023YFC3403200);National Natural Science Foundation of China(82070784,81702536,81974099 and 82170785);Science&Technology Department of Sichuan Province,China(2022JDRC0040,21GJHZ0246);Young Investigator Award of Sichuan University 2017(2017SCU04A17);Sichuan University-Panzhihua Science and Technology Cooperation Special Fund(2020CDPZH-4);China Postdoctoral Science Foundation(2021M692306);Post-Doctor Research Project of West China Hospital of Sichuan University(2021HXBH025).

摘　　要：Background Cell metabolism plays a pivotal role in tumor progression,and targeting cancer metabolism might effectively kill cancer cells.We aimed to investigate the role of hexokinases in prostate cancer(PCa)and identify a crucial target for PCa treatment.Methods The Cancer Genome Atlas(TCGA)database,online tools and clinical samples were used to assess the expression and prognostic role of ADP-dependent glucokinase(ADPGK)in PCa.The effect of ADPGK expression on PCa cell malignant phenotypes was validated in vitro and in vivo.Quantitative proteomics,metabolomics,and extracellular acidification rate(ECAR)and oxygen consumption rate(OCR)tests were performed to evaluate the impact of ADPGK on PCa metabolism.The underlying mechanisms were explored through ADPGK overexpression and knockdown,co-immunoprecipitation(Co-IP),ECAR analysis and cell counting kit-8(CCK-8)assays.Results ADPGK was the only glucokinase that was both upregulated and predicted worse overall survival(OS)in prostate adenocarcinoma(PRAD).Clinical sample analysis demonstrated that ADPGK was markedly upregulated in PCa tissues vs.non-PCa tissues.High ADPGK expression indicates worse survival outcomes,and ADPGK serves as an independent factor of biochemical recurrence.In vitro and in vivo experiments showed that ADPGK overexpression promoted PCa cell proliferation and migration,and ADPGK inhibition suppressed malignant phenotypes.Metabolomics,proteomics,and ECAR and OCR tests revealed that ADPGK significantly accelerated glycolysis in PCa.Mechanistically,ADPGK binds aldolase C(ALDOC)to promote glycolysis via AMP-activated protein kinase(AMPK)phosphorylation.ALDOC was positively correlated with ADPGK,and high ALDOC expression was associated with worse survival outcomes in PCa.Conclusions In summary,ADPGK is a driving factor in PCa progression,and its high expression contributes to a poor prognosis in PCa patients.ADPGK accelerates PCa glycolysis and progression by activating ALDOC-AMPK signaling,suggesting that ADPGK might be an effective target and mark

关 键 词：Prostate cancer(PCa) ADP-dependent glucokinase(ADPGK) Aldolase C(ALDOC) AMPK Glycolysis 

分 类 号：R737.25[医药卫生—肿瘤]