Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, China.
Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, China; Cancer Center, Zhejiang University, China.
Biochem Biophys Res Commun. 2023 Sep 3;671:46-57. doi: 10.1016/j.bbrc.2023.05.097. Epub 2023 Jun 1.
Targeting oxidative phosphorylation (OXPHOS) has emerged as a strategy for cancer treatment. However, most tumor cells exhibit Warburg effect, they primarily rely on glycolysis to generate ATP, and hence they are resistant to OXPHOS inhibitors. Here, we report that lactic acidosis, a ubiquitous factor in the tumor microenvironment, increases the sensitivity of glycolysis-dependent cancer cells to OXPHOS inhibitors by 2-4 orders of magnitude. Lactic acidosis reduces glycolysis by 79-86% and increases OXPHOS by 177-218%, making the latter the main production pathway of ATP. In conclusion, we revealed that lactic acidosis renders cancer cells with typical Warburg effect phenotype highly sensitive to OXPHOS inhibitors, thereby greatly expanding the anti-cancer spectrum of OXPHOS inhibitors. In addition, as lactic acidosis is a ubiquitous factor of TME, it is a potential indicator to predict the efficacy of OXPHOS inhibitors in cancer treatment.
靶向氧化磷酸化（OXPHOS）已成为癌症治疗的一种策略。然而，大多数肿瘤细胞表现出瓦博格效应，它们主要依赖糖酵解来产生 ATP，因此对 OXPHOS 抑制剂具有抗性。在这里，我们报告了肿瘤微环境中普遍存在的乳酸酸中毒通过 2-4 个数量级增加了依赖糖酵解的癌细胞对 OXPHOS 抑制剂的敏感性。乳酸酸中毒使糖酵解降低 79-86%，并使 OXPHOS 增加 177-218%，使后者成为 ATP 的主要产生途径。总之，我们揭示了乳酸酸中毒使具有典型瓦博格效应表型的癌细胞对 OXPHOS 抑制剂高度敏感，从而大大扩大了 OXPHOS 抑制剂的抗癌谱。此外，由于乳酸酸中毒是 TME 的普遍因素，它是预测 OXPHOS 抑制剂在癌症治疗中疗效的一个潜在指标。
