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, Hangzhou, China.
Interventional Radiology, Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Oncogene. 2022 Jul;41(31):3886-3897. doi: 10.1038/s41388-022-02396-6. Epub 2022 Jul 2.
We previously found that lactic acidosis in the tumor environment was permissive to cancer cell surviving under glucose deprivation and demonstrated that neutralizing lactic acidosis restored cancer cell susceptibility to glucose deprivation. We then reported that alternate infusion of bicarbonate and anticancer agent into tumors via tumor feeding artery markedly enhanced the efficacy of transarterial chemoembolization (TACE) in the local control of hepatocellular carcinoma (HCC). Here we sought to further investigate the mechanism by which bicarbonate enhances the anticancer activity of TACE. We propose that interfering cellular pH by bicarbonate could induce a cascade of molecular events leading to cancer cell death. Alkalizing cellular pH by bicarbonate decreased pH gradient (ΔpH), membrane potential (ΔΨ), and proton motive force (Δp) across the inner membrane of mitochondria; disruption of oxidative phosphorylation (OXPHOS) due to collapsed Δp led to a significant increase in adenosine monophosphate (AMP), which activated the classical AMPK-mediated autophagy. Meanwhile, the autophagic flux was ultimately blocked by increased cellular pH, reduced OXPHOS, and inhibition of lysosomal proton pump in alkalized lysosome. Bicarbonate also induced persistent mitochondrial permeability (MPT) and damaged mitochondria. Collectively, this study reveals that interfering cellular pH may provide a valuable approach to treat cancer.
我们之前发现肿瘤微环境中的乳酸酸中毒有利于癌细胞在葡萄糖剥夺条件下存活，并证实中和乳酸酸中毒可恢复癌细胞对葡萄糖剥夺的敏感性。随后我们报道称，通过肿瘤供养动脉向肿瘤内交替输注碳酸氢盐和抗癌药物可显著增强经动脉化疗栓塞术（TACE）治疗肝细胞癌（HCC）的局部控制效果。在此，我们试图进一步研究碳酸氢盐增强 TACE 抗癌活性的机制。我们提出，碳酸氢盐通过干扰细胞 pH 值可诱导一系列分子事件，导致癌细胞死亡。碳酸氢盐使细胞 pH 值碱化会降低线粒体内膜的 pH 梯度（ΔpH）、膜电位（ΔΨ）和质子动力势（Δp）；由于 Δp 崩溃导致氧化磷酸化（OXPHOS）中断，会导致腺苷一磷酸（AMP）显著增加，从而激活经典的 AMPK 介导的自噬。同时，由于细胞 pH 值升高、OXPHOS 减少以及溶酶体质子泵在碱化溶酶体中的抑制作用，自噬通量最终被阻断。碳酸氢盐还可诱导持续的线粒体通透性（MPT）和受损的线粒体。总之，这项研究揭示了干扰细胞 pH 值可能为治疗癌症提供一种有价值的方法。
