Glycolysis maintains AMPK activation in sorafenib-induced Warburg effect.

Hepatocellular carcinoma (HCC) is the second deadly cancer in the world and still lacks curative treatment. Aerobic glycolysis, or Warburg effect, is a major resistance mechanism induced by first-line treatment of HCC, sorafenib, and is regulated by the master regulator of metabolism, AMPK. Activation of AMPK is required for resistance; however, activation dynamics of AMPK and its regulation is rarely studied. Engineering cells to express an AMPK activity biosensor, we monitor AMPK activation in single HCC cells in a high throughput manner during sorafenib-induced drug resistance. Sorafenib induces transient activation of AMPK, duration of which is dependent on glucose. Inhibiting glycolysis shortens AMPK activation; whereas increasing glycolysis increases its activation duration. Our data highlight that activation duration of AMPK is important for cancer evasion of therapeutic treatment and glycolysis is a key regulator of activation duration of AMPK.

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Copyright © 2023. Published by Elsevier GmbH.

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Declaration of Competing Interest This study was supported by the National Natural Science Foundation of China (Grant No. 881973403, 81841003), Peking University Seed Fund for Medicine-Information Interdisciplinary Research Project (Grant No. BMU2020MI004), Peking University Health Science Center Start-up Project (Grant No. BMU2018YJ012, BMU2021YJ053). We are deeply grateful to Professor John Albeck from University of California Davis to share with us the AMPKAR2 plasmid. We thank Dr. Han Xiao from the Third hospital of Peking University for many fruitful discussions and thoughtful advice. We thank Dr. Jia-Ren Lin from Laboratory of Systems Pharmacology at Harvard Medical School for great suggestions in Image analysis and deposition. We thank Yiming Wang and Songmin Liu for being nice colleagues and help in the lab. We thank Megarobo Inc. (Beijing, China) for their support in high-content fluorescence microscope imaging. We thank the Facility Center of Metabolomics and Lipidomics of China National Center for Protein Sciences (Tsinghua University) for the metabolomics profiling. There is no conflict of interest to declare for any author.