ADP-dependent glucokinase controls metabolic fitness in prostate cancer progression

Abstract

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.

Current status and progress of research on the ADP-dependent glucokinase gene

“…Biological functions: 1. ADPGK is involved in glycolysis, ADPGK overexpression significantly promotes the process of glycolysis, and the overproduction of lactate induced by the Warburg effect further induces the cancer progression ( 33 ); 2. ADPGK can activate T cells.…”

“…Hang Xu et al. ( 33 ) discovered in 2023 that ADPGK drives prostate cancer progression and high expression of it leads to poor prognosis in patients. ADPGK can accelerate prostate cancer glycolysis and progression through activation of ALDOC-AMPK signaling.…”

Xihuang pills targeting the Warburg effect through inhibition of the Wnt/β-catenin pathway in prostate cancer

“…Studies suggest that early PCa cells prefer lipids and alternative energy sources, leaning more towards oxidative phosphorylation (OXPHOS) rather than glycolysis [ 42 ]. However, reports consistently point to a metabolic shift in advanced PCa, especially in aggressive, metastatic, castration-resistant cases [ 43 , 44 ]. Mechanisms involved in the development of CRPC are diverse, encompassing AR gene amplification, overexpression, and mutations leading to constitutive or promiscuous activity [ 45 , 46 ].…”