Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, New York 10965, USA.
Annu Rev Pharmacol Toxicol. 2013;53:89-106. doi: 10.1146/annurev-pharmtox-010611-134717.
A fundamental imperative for mammalian cells is to coordinate cell metabolism and growth with environmentally induced stress. This review focuses on three highly integrated networks-the phosphoinositide 3-kinase (PI3K) signaling cascade, intermediate metabolism, and autophagy-that work together to maintain cellular homeostasis under basal conditions and to drive cell-mass accumulation and cell cycle progression in the presence of appropriate mitogenic stimuli. Dysfunction within any one of these networks results in compensatory responses from the other networks. These responses underpin several pathologies associated with major human diseases such as cancer. We discuss the PI3K, metabolism, and autophagy networks and provide selected insights into internetwork cross-talk mechanisms. In recognition of the extensive interactions observed in both healthy and diseased cells, we propose that the three networks be merged into a "metabolism-signaling supernetwork." A detailed understanding of this supernetwork will facilitate the development of novel therapies for cancer and other complex diseases.
哺乳动物细胞的一个基本要求是协调细胞代谢和生长与环境诱导的应激。本篇综述聚焦于三个高度整合的网络——磷酸肌醇 3-激酶（PI3K）信号级联、中间代谢和自噬——它们共同作用，在基础条件下维持细胞内稳态，并在适当的有丝分裂刺激下驱动细胞质量积累和细胞周期进程。这些网络中的任何一个功能失调都会导致其他网络的代偿反应。这些反应是与癌症等重大人类疾病相关的几种病理学的基础。我们讨论了 PI3K、代谢和自噬网络，并提供了对网络间交叉对话机制的精选见解。鉴于在健康和患病细胞中观察到的广泛相互作用，我们建议将这三个网络合并为一个“代谢-信号超级网络”。对这个超级网络的详细了解将有助于为癌症和其他复杂疾病开发新的治疗方法。
