Abstract
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 (ΔΨm), 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.
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Acknowledgements
This work has been supported in part by China Natural Sciences Foundation projects (82073038, 81772947 to XH), a key project (2018C03009) funded by Zhejiang Provincial Department of Sciences and Technologies (to XH & MC), and the Fundamental Research Funds for the Central Universities (2017XZZX001-01, 2019FZJD009, to XH), National Ministry of Education, China. We thank Dr. Guo-Hua Fong (University of Connecticut School of Medicine, USA) for critical readings of our manuscript and constructive comments, Dr. Wei Liu (Zhejiang University) for the kind gift of plasmids GFP-LC3, Cherry-GFP-LC3, and Dr. Shanrong Cai for the statistical assistance (Zhejiang University).
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XH conceived the project, designed the study, analyzed the data, wrote the manuscript. CY & CJ. performed the experiments, CY, CJ, SZ. analyzed the data, MC, analysis of MRI images.
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Ying, C., Jin, C., Zeng, S. et al. Alkalization of cellular pH leads to cancer cell death by disrupting autophagy and mitochondrial function. Oncogene 41, 3886–3897 (2022). https://doi.org/10.1038/s41388-022-02396-6
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DOI: https://doi.org/10.1038/s41388-022-02396-6
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