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Targeting aldolase A in hepatocellular carcinoma leads to imbalanced glycolysis and energy stress due to uncontrolled FBP accumulation
Nature Metabolism ( IF 18.9 ) Pub Date : 2025-01-20 , DOI: 10.1038/s42255-024-01201-w
Marteinn T. Snaebjornsson, Philipp Poeller, Daria Komkova, Florian Röhrig, Lisa Schlicker, Alina M. Winkelkotte, Adriano B. Chaves-Filho, Kamal M. Al-Shami, Carolina Dehesa Caballero, Ioanna Koltsaki, Felix C. E. Vogel, Roberto Carlos Frias-Soler, Ramona Rudalska, Jessica D. Schwarz, Elmar Wolf, Daniel Dauch, Ralf Steuer, Almut Schulze

Increased glycolytic flux is a hallmark of cancer; however, an increasing body of evidence indicates that glycolytic ATP production may be dispensable in cancer, as metabolic plasticity allows cancer cells to readily adapt to disruption of glycolysis by increasing ATP production via oxidative phosphorylation. Using functional genomic screening, we show here that liver cancer cells show a unique sensitivity toward aldolase A (ALDOA) depletion. Targeting glycolysis by disrupting the catalytic activity of ALDOA led to severe energy stress and cell cycle arrest in murine and human hepatocellular carcinoma cell lines. With a combination of metabolic flux analysis, metabolomics, stable-isotope tracing and mathematical modelling, we demonstrate that inhibiting ALDOA induced a state of imbalanced glycolysis in which the investment phase outpaced the payoff phase. Targeting ALDOA effectively converted glycolysis from an energy producing into an energy-consuming process. Moreover, we found that depletion of ALDOA extended survival and reduced cancer cell proliferation in an animal model of hepatocellular carcinoma. Thus, our findings indicate that induction of imbalanced glycolysis by targeting ALDOA presents a unique opportunity to overcome the inherent metabolic plasticity of cancer cells.



中文翻译:


在肝细胞癌中靶向醛缩酶 A 会导致糖酵解不平衡和能量应激,这是由于 FBP 积累不受控制



糖酵解通量增加是癌症的标志;然而,越来越多的证据表明,糖酵解 ATP 的产生在癌症中可能是必不可少的,因为代谢可塑性使癌细胞能够通过氧化磷酸化增加 ATP 的产生来轻松适应糖酵解的破坏。使用功能基因组筛选,我们在这里表明肝癌细胞对醛缩酶 A (ALDOA) 耗竭表现出独特的敏感性。通过破坏 ALDOA 的催化活性来靶向糖酵解导致小鼠和人肝细胞癌细胞系中严重的能量应激和细胞周期停滞。通过结合代谢通量分析、代谢组学、稳定同位素示踪和数学建模,我们证明抑制 ALDOA 诱导了一种不平衡的糖酵解状态,其中投资阶段超过了回报阶段。靶向 ALDOA 有效地将糖酵解从能量产生转化为能量消耗过程。此外,我们发现 ALDOA 的耗竭延长了肝细胞癌动物模型的生存期并减少了癌细胞增殖。因此,我们的研究结果表明,通过靶向 ALDOA 诱导不平衡的糖酵解为克服癌细胞固有的代谢可塑性提供了独特的机会。

更新日期:2025-01-20
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