Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis
Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis
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DOI：
10.1016/j.ccell.2019.03.007
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发表时间：
2019-05-13
期刊：
影响因子：
50.3
通讯作者：
Minucci, Saverio
中科院分区：
文献类型：
--
作者：
Elgendy, Mohamed;Ciro, Marco;Minucci, Saverio
肿瘤细胞可以通过糖酵解和氧化磷酸化（OXPHOS）之间的交替来适应代谢挑战。为了针对这种代谢可塑性，我们将间歇性禁食（一种临床上可行的降低葡萄糖可用性的方法）与OXPHOS抑制剂二甲双胍相结合。在暴露于24小时喂养/禁食周期的小鼠中，二甲双胍仅在禁食诱导的低血糖期间给药时才损害肿瘤生长。二甲双胍/低血糖联合用药的协同抗肿瘤作用由PP 2A下游的糖原合成酶激酶3 β（GSK 3 β）激活介导，导致促生存蛋白MCL-1下降和细胞死亡。从机制上讲，PP 2A-GSK 3 β轴的特异性激活是二甲双胍诱导的CIP 2A抑制（PP 2A抑制剂）和低葡萄糖上调PP 2A调节亚基B56 δ的总和，导致对GSK 3 β具有高亲和力的活性PP 2A-B568 δ复合物。
Tumor cells may adapt to metabolic challenges by alternating between glycolysis and oxidative phosphorylation (OXPHOS). To target this metabolic plasticity, we combined intermittent fasting, a clinically feasible approach to reduce glucose availability, with the OXPHOS inhibitor metformin. In mice exposed to 24-h feeding/fasting cycles, metformin impaired tumor growth only when administered during fasting-induced hypoglycemia. Synergistic anti-neoplastic effects of the metformin/hypoglycemia combination were mediated by glycogen synthase kinase 3 beta (GSK3 beta) activation downstream of PP2A, leading to a decline in the pro-survival protein MCL-1, and cell death. Mechanistically, specific activation of the PP2A-GSK3 beta axis was the sum of metformin-induced inhibition of CIP2A, a PP2A suppressor, and of upregulation of the PP2A regulatory subunit B56 delta by low glucose, leading to an active PP2A-B568 delta complex with high affinity toward GSK3 beta.