The December 2023 issue of the Military Medical Research brings out an astounding discover y by Xu et al.[1]demonstrating a key role of the mysterious enzyme ADPdependent glucokinase(ADPGK)in the cellular metabolism o...The December 2023 issue of the Military Medical Research brings out an astounding discover y by Xu et al.[1]demonstrating a key role of the mysterious enzyme ADPdependent glucokinase(ADPGK)in the cellular metabolism of prostate cancer(PCa).The ADPGKs are enzymes typically found in thermophilic archaea where they mediate the indispensable,first step of glucose metabolism,i.e.phosphorylation of glucose to glucose-6-phosphate.Strikingly,ADPGKs utilize ADP as a phosphate donor instead of ATP typically used to initiate glycolysis by four“classical”eukaryotic hexokinases(HKⅠ–Ⅲand glucokinase).Thus,the discovery made by Ronimus and Morgan[2]of the functional form of ADPGK in mice,opened an intriguing question of the specific role of this enzyme in the metabolism of eukaryotic cell.展开更多
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 ident...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 marker for PCa treatment and prognosis evaluation.展开更多
文摘The December 2023 issue of the Military Medical Research brings out an astounding discover y by Xu et al.[1]demonstrating a key role of the mysterious enzyme ADPdependent glucokinase(ADPGK)in the cellular metabolism of prostate cancer(PCa).The ADPGKs are enzymes typically found in thermophilic archaea where they mediate the indispensable,first step of glucose metabolism,i.e.phosphorylation of glucose to glucose-6-phosphate.Strikingly,ADPGKs utilize ADP as a phosphate donor instead of ATP typically used to initiate glycolysis by four“classical”eukaryotic hexokinases(HKⅠ–Ⅲand glucokinase).Thus,the discovery made by Ronimus and Morgan[2]of the functional form of ADPGK in mice,opened an intriguing question of the specific role of this enzyme in the metabolism of eukaryotic cell.
基金National Key R&D Plan(2023YFC3403200)National Natural Science Foundation of China(82070784,81702536,81974099 and 82170785)+4 种基金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).
文摘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 marker for PCa treatment and prognosis evaluation.
