AMPK-deficiency forces metformin-challenged cancer cells to switch from carbohydrate metabolism to ketogenesis to support energy metabolism.
AMPK-deficiency forces metformin-challenged cancer cells to switch from carbohydrate metabolism to ketogenesis to support energy metabolism.
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AMPK缺乏迫使二甲双胍攻击的癌细胞从碳水化合物代谢转变为酮生成以支持能量代谢。
DOI：
10.1038/s41388-021-01943-x
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发表时间：
2021-09
期刊：
影响因子：
8
通讯作者：
Bonini MG
中科院分区：
文献类型：
--
作者：
Palma FR;Ratti BA;Paviani V;Coelho DR;Miguel R;Danes JM;Zaichik SV;de Abreu AL;Silva SO;Chen Y;Silverstein RL;Karan U;Jones DP;Bonini MG
对糖尿病患者的流行病学研究以及对模型生物的研究表明二甲双胍作为治疗各种癌症（包括乳腺癌）的候选药物的潜力。迄今为止，二甲双胍的大部分抗癌特性在很大程度上归因于对线粒体 NADH 氧化酶复合物（电子传递链中的复合物 I）的抑制或 AMP 激活激酶 (AMPK) 的激活。然而，越来越清楚的是，AMPK 激活可能对于缓解与肿瘤进展相关的代谢和能量应激至关重要，这表明它实际上可能减弱而不是促进二甲双胍的毒性。在这里，我们证明 AMPK 通过增强糖酵解来对抗线粒体复合物 I 抑制的有害影响，但以牺牲丙酮酸可用性为代价，并以一种依赖于丙酮酸可用性的方式。我们还发现二甲双胍迫使细胞以依赖于 AMPK 的方式重新连接其代谢网格，具有 AMPK 活性的细胞上调糖酵解，而 AMPK 缺陷的细胞则诉诸生酮作用。事实上，虽然二甲双胍的杀伤作用在 AMPK 感受态细胞中很大程度上被丙酮酸所挽救，但 AMPK 缺陷的细胞需要乙酰乙酸，乙酰乙酸是脂肪酸分解代谢的产物，表明这些细胞从糖转向脂肪酸作为 ATP 的主要来源。总之，我们的结果表明 AMPK 激活并不负责二甲双胍的抗癌活性，而是可能通过激活糖酵解来缓解能量应激。
Epidemiologic studies in diabetic patients as well as research in model organisms have indicated the potential of metformin as a drug candidate for the treatment of various types of cancer, including breast cancer. To date most of the anti-cancer properties of metformin have, in large part, been attributed either to the inhibition of mitochondrial NADH oxidase complex (Complex I in the electron transport chain) or the activation of AMP-activated kinase (AMPK). However, it is becoming increasingly clear that AMPK activation may be critical to alleviate metabolic and energetic stresses associated with tumor progression suggesting that it may, in fact, attenuate the toxicity of metformin instead of promoting it. Here, we demonstrate that AMPK opposes the detrimental effects of mitochondrial complex I inhibition by enhancing glycolysis at the expense of, and in a manner dependent on, pyruvate availability. We also found that metformin forces cells to rewire their metabolic grid in a manner that depends on AMPK, with AMPK-competent cells upregulating glycolysis and AMPK-deficient cell resorting to ketogenesis. In fact while the killing effects of metformin were largely rescued by pyruvate in AMPK competent cells, AMPK-deficient cells required instead acetoacetate, a product of fatty acid catabolism indicating a switch from sugar to fatty acid as a central source of ATP for these cells. In summary, our results indicate that AMPK activation is not responsible for metformin anticancer activity and may instead alleviate energetic stress by activating glycolysis.
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