Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
National Key Laboratory of Science and Technology on Micro/Nano Fabrication, School of Integrated Circuit, Peking University, Beijing, 100871, China.
Mol Metab. 2023 Nov;77:101796. doi: 10.1016/j.molmet.2023.101796. Epub 2023 Sep 9.
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.
肝细胞癌（HCC）是全球第二大致命癌症，目前仍缺乏有效的治疗方法。有氧糖酵解，即瓦博格效应，是 HCC 一线治疗药物索拉非尼诱导产生耐药性的主要机制，受代谢关键调控因子 AMPK 调控。AMPK 的激活是产生耐药性的必要条件；然而，AMPK 的激活动力学及其调控很少被研究。通过工程细胞表达 AMPK 活性生物传感器，我们以高通量的方式在索拉非尼诱导的耐药性过程中监测单个 HCC 细胞中的 AMPK 激活。索拉非尼诱导 AMPK 的短暂激活，其持续时间取决于葡萄糖。抑制糖酵解会缩短 AMPK 的激活；而增加糖酵解则会延长其激活时间。我们的数据强调了 AMPK 的激活持续时间对于癌症逃避治疗的重要性，糖酵解是调节 AMPK 激活持续时间的关键因素。
