Robey R B, Hay N
Research and Development Service, White River Junction VA Medical Center, White River Junction, VT 05009-0001, USA.
Oncogene. 2006 Aug 7;25(34):4683-96. doi: 10.1038/sj.onc.1209595.
Cell survival has been closely linked to both trophic growth factor signaling and cellular metabolism. Such couplings have obvious physiologic and pathophysiologic implications, but their underlying molecular bases remain incompletely defined. As a common mediator of both the metabolic and anti-apoptotic effects of growth factors, the serine/threonine kinase Akt - also known as protein kinase B or PKB - is capable of regulating and coordinating these inter-related processes. The glucose dependence of the antiapoptotic effects of growth factors and Akt plus a strong correlation between Akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects. Mitochondrial hexokinases catalyse the first obligatory step of glucose metabolism and directly couple extramitochondrial glycolysis to intramitochondrial oxidative phosphorylation, and are thus well suited to play this role. The ability of Akt to regulate energy metabolism appears to have evolutionarily preceded the capacity to control cell survival. This suggests that Akt-dependent metabolic regulatory functions may have given rise to glucose-dependent antiapoptotic effects that evolved as an adaptive sensing system involving hexokinases and serve to ensure mitochondrial homeostasis, thereby coupling metabolism to cell survival. We hypothesize that the enlistment of Akt and hexokinase in the control of mammalian cell apoptosis evolved as a response to the recruitment of mitochondria to the apoptotic cascade. The central importance of mitochondrial hexokinases in cell survival also suggests that they may represent viable therapeutic targets in cancer.
细胞存活与营养生长因子信号传导和细胞代谢都密切相关。这种耦合具有明显的生理和病理生理意义，但其潜在的分子基础仍未完全明确。作为生长因子代谢和抗凋亡作用的共同介质，丝氨酸/苏氨酸激酶Akt（也称为蛋白激酶B或PKB）能够调节和协调这些相互关联的过程。生长因子和Akt的抗凋亡作用对葡萄糖的依赖性，以及Akt调节的线粒体己糖激酶结合与凋亡易感性之间的强相关性，表明己糖激酶在这些作用中起主要作用。线粒体己糖激酶催化葡萄糖代谢的第一步，并直接将线粒体外糖酵解与线粒体内氧化磷酸化偶联起来，因此非常适合发挥这一作用。Akt调节能量代谢的能力在进化上似乎先于其控制细胞存活的能力。这表明，Akt依赖的代谢调节功能可能产生了葡萄糖依赖性抗凋亡作用，这种作用作为一种涉及己糖激酶的适应性传感系统而进化，并有助于确保线粒体稳态，从而将代谢与细胞存活联系起来。我们假设，Akt和己糖激酶参与哺乳动物细胞凋亡的控制是对线粒体被招募到凋亡级联反应的一种反应。线粒体己糖激酶在细胞存活中的核心重要性也表明，它们可能是癌症中可行的治疗靶点。
