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. 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. 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. 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.

中文翻译：

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ADP 依赖性葡萄糖激酶控制前列腺癌进展中的代谢适应性

细胞代谢在肿瘤进展中发挥着关键作用，靶向癌症代谢可能会有效杀死癌细胞。我们的目的是研究己糖激酶在前列腺癌 (PCa) 中的作用并确定 PCa 治疗的关键靶点。癌症基因组图谱 (TCGA) 数据库、在线工具和临床样本用于评估 PCa 中 ADP 依赖性葡萄糖激酶 (ADPGK) 的表达和预后作用。ADPGK 表达对 PCa 细胞恶性表型的影响在​​体外和体内得到验证。通过定量蛋白质组学、代谢组学以及细胞外酸化率 (ECAR) 和耗氧率 (OCR) 测试来评估 ADPGK 对 PCa 代谢的影响。通过 ADPGK 过表达和敲低、免疫共沉淀 (Co-IP)、ECAR 分析和细胞计数试剂盒 8 (CCK-8) 分析探索了潜在机制。ADPGK 是唯一一种在前列腺腺癌 (PRAD) 中既上调又预测总生存期 (OS) 较差的葡萄糖激酶。临床样本分析表明，与非 PCa 组织相比，ADPGK 在 PCa 组织中显着上调。ADPGK 高表达表明生存结果较差，ADPGK 是生化复发的独立因素。体外和体内实验表明，ADPGK过表达促进PCa细胞增殖和迁移，抑制ADPGK可抑制恶性表型。代谢组学、蛋白质组学以及 ECAR 和 OCR 测试表明 ADPGK 显着加速 PCa 中的糖酵解。从机制上讲，ADPGK 结合醛缩酶 C (ALDOC)，通过 AMP 激活蛋白激酶 (AMPK) 磷酸化促进糖酵解。ALDOC 与 ADPGK 呈正相关，且 ALDOC 高表达与 PCa 较差的生存结果相关。综上所述，ADPGK是PCa进展的驱动因素，其高表达导致PCa患者预后不良。ADPGK 通过激活 ALDOC-AMPK 信号传导加速 PCa 糖酵解和进展，表明 ADPGK 可能是 PCa 治疗和预后评估的有效靶点和标志物。