Translational Research Laboratory, Catalan Institute of Oncology (ICO), Girona, Spain.
Cell Cycle. 2012 Mar 1;11(5):974-89. doi: 10.4161/cc.11.5.19450.
The ability of somatic cells to reprogram their ATP-generating machinery into a Warburg-like glycolytic metabotype while overexpressing stemness genes facilitates their conversion into either induced pluripotent stem cells (iPSCs) or tumor-propagating cells. AMP-activated protein kinase (AMPK) is a metabolic master switch that senses and decodes intracellular changes in energy status; thus, we have evaluated the impact of AMPK activation in regulating the generation of iPSCs from nonstem cells of somatic origin. The indirect and direct activation of AMPK with the antidiabetic biguanide metformin and the thienopyridone A-769662, respectively, impeded the reprogramming of mouse embryonic and human diploid fibroblasts into iPSCs. The AMPK activators established a metabolic barrier to reprogramming that could not be bypassed, even through p53 deficiency, a fundamental mechanism to greatly improve the efficiency of stem-cell production. Treatment with metformin or A-769662 before the generation of iPSC colonies was sufficient to drastically decrease iPSC generation, suggesting that AMPK activation impedes early stem cell genetic reprogramming. Monitoring the transcriptional activation status of each individual reprogramming factor (i.e., Oct4, Sox2, Klf4 and c-Myc) revealed that AMPK activation notably prevented the transcriptional activation of Oct4, the master regulator of the pluripotent state. AMPK activation appears to impose a normalized metabolic flow away from the required pro-immortalizing glycolysis that fuels the induction of stemness and pluripotency, endowing somatic cells with an energetic infrastructure that is protected against reprogramming. AMPK-activating anti-reprogramming strategies may provide a roadmap for the generation of novel cancer therapies that metabolically target tumor-propagating cells.
体细胞在过表达干性基因的同时，重新编程其 ATP 生成机制，使其转变为类似于瓦博格（Warburg）的糖酵解代谢类型，从而促进其转化为诱导多能干细胞（iPSCs）或肿瘤增殖细胞。AMP 激活的蛋白激酶（AMPK）是一种代谢主开关，能够感知和解码细胞内能量状态的变化；因此，我们评估了 AMPK 激活对调节非干性体细胞生成 iPSCs 的影响。通过使用抗糖尿病双胍类药物二甲双胍和噻吩并吡啶 A-769662 间接和直接激活 AMPK，分别抑制了小鼠胚胎和成纤维细胞向 iPSCs 的重编程。AMPK 激活剂为重编程建立了代谢障碍，即使通过 p53 缺陷这一极大提高干细胞生成效率的基本机制，也无法绕过这一障碍。在 iPSC 集落生成之前用二甲双胍或 A-769662 处理足以显著降低 iPSC 的生成，表明 AMPK 激活会阻碍早期干细胞遗传重编程。监测每个重编程因子（即 Oct4、Sox2、Klf4 和 c-Myc）的转录激活状态表明，AMPK 激活显著阻止了多能状态的主调控因子 Oct4 的转录激活。AMPK 激活似乎会迫使代谢流正常化，远离需要的促进永生的糖酵解，为体细胞提供免受重编程影响的能量基础设施。激活 AMPK 的抗重编程策略可能为代谢靶向肿瘤增殖细胞的新型癌症治疗提供新的思路。
