Haikala Heidi M, Anttila Johanna M, Klefström Juha
Research Programs Unit/Translational Cancer Biology, Cancer Cell Circuitry Laboratory, Institute of Biomedicine, University of HelsinkiHelsinki, Finland.
Front Cell Dev Biol. 2017 Apr 11;5:38. doi: 10.3389/fcell.2017.00038. eCollection 2017.
MYC sustains non-stop proliferation by altering metabolic machinery to support growth of cell mass. As part of the metabolic transformation MYC promotes lipid, nucleotide and protein synthesis by hijacking citric acid cycle to serve biosynthetic processes, which simultaneously exhausts ATP production. This leads to the activation of cellular energy sensing protein, AMP-activated protein kinase (AMPK). Cells with normal growth control can stop cell proliferation machinery to replenish ATP reservoirs whereas MYC prevents such break by blocking the cell cycle exit. The relentless cell cycle activation, accompanied by sustained metabolic stress and AMPK activity, switches the energy-saving AMPK to pro-apoptotic AMPK. The AMPK-involving metabolic side of MYC apoptosis may provide novel avenues for therapeutic development. Here we first review the role of anabolic MYC and catabolic AMPK pathways in context of cancer and then discuss how the concomitant activity of both pathways in tumor cells may result in targetable synthetic lethal vulnerabilities.
MYC 通过改变代谢机制来维持不间断的增殖，以支持细胞质量的增长。作为代谢转变的一部分，MYC 通过劫持柠檬酸循环来促进脂质、核苷酸和蛋白质合成，以服务于生物合成过程，这同时耗尽了 ATP 的产生。这导致细胞能量感应蛋白——AMP 激活蛋白激酶（AMPK）的激活。具有正常生长控制的细胞可以停止细胞增殖机制以补充 ATP 储备，而 MYC 通过阻止细胞周期退出防止这种中断。持续的细胞周期激活，伴随着持续的代谢应激和 AMPK 活性，将节能型 AMPK 转变为促凋亡型 AMPK。MYC 凋亡中涉及 AMPK 的代谢方面可能为治疗开发提供新途径。在这里，我们首先回顾合成代谢的 MYC 和分解代谢的 AMPK 途径在癌症背景下的作用，然后讨论这两种途径在肿瘤细胞中的协同活性如何可能导致可靶向的合成致死性弱点。
