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ADP-abhängige Glukokinase steuert die metabolische Fitness beim Fortschreiten des Prostatakarzinoms

  • role： Contribute equally, First author同等贡献者, 第一作者
  • Affiliation：

    Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

    Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

Hang Xu12,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

    Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

Yi-Fan Li12,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

    Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

Xian-Yan-Ling Yi12,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

    Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

Xiao-Nan Zheng12,  
  • Affiliation：

    Animal Experimental Center, West China Hospital, Sichuan University, Chengdu 610041, China

Yang Yang3,  
  • Affiliation：

    Research Core Facility, West China Hospital, Sichuan University, Chengdu 610041, China

Yan Wang4,  
  • Affiliation：

    Research Core Facility, West China Hospital, Sichuan University, Chengdu 610041, China

Da-Zhou Liao4,  
  • Affiliation：

    Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

    Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

Jia-Peng Zhang12,  
  • Affiliation：

    Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

    Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

Ping Tan12,  
  • Affiliation：

    Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

    Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

Xing-Yu Xiong12,  
  • Affiliation：

    Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

    Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

Xi Jin12,  
  • Affiliation：

    Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

    Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

Li-Na Gong12,  
  • Affiliation：

    Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

    Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

Shi Qiu12,  
  • Affiliation：

    Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

    Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

De-Hong Cao12,  
  • Affiliation：

    Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

    Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

Hong Li12,  
  • role： Corresponding author通信作者
  • Affiliation：

    Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

    Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

  • Email：weiqiang@scu.edu.cn
  • Introduction：*weiqiang@scu.edu.cn;
Qiang Wei12*,  
  • role： Corresponding author通信作者
  • Affiliation：

    Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

    Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

  • Email：wycleflue@scu.edu.cn
  • Introduction：wycleflue@scu.edu.cn;
Lu Yang12*,  
  • role： Corresponding author通信作者
  • Affiliation：

    Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

    Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

  • Email：jianzhong.ai@scu.edu.cn
  • Introduction：jianzhong.ai@scu.edu.cn
Jian-Zhong Ai12*

Resümee

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.

Schlüsselwort

Prostate cancer (PCa);ADP-dependent glucokinase (ADPGK);Aldolase C (ALDOC);AMPK;Glycolysis

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