Chuang Hsiao-Ching, Chou Chih-Chien, Kulp Samuel K, Chen Ching-Shih
Rm 336, Parks Hall, College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, OH 43210, USA.
Curr Pharm Des. 2014;20(15):2607-18. doi: 10.2174/13816128113199990485.
Adenosine monophosphate-activated protein kinase (AMPK) is a key player in maintaining energy homeostasis in response to metabolic stress. Beyond diabetes and metabolic syndrome, there is a growing interest in the therapeutic exploitation of the AMPK pathway in cancer treatment in light of its unique ability to regulate cancer cell proliferation through the reprogramming of cell metabolism. Although many studies support the tumor-suppressive role of AMPK, emerging evidence suggests that the metabolic checkpoint function of AMPK might be overridden by stress or oncogenic signals so that tumor cells use AMPK activation as a survival strategy to gain growth advantage. These findings underscore the complexity in the cellular function of AMPK in maintaining energy homeostasis under physiological versus pathological conditions. Thus, this review aims to provide an overview of recent findings on the functional interplay of AMPK with different cell metabolic and signaling effectors, particularly histone deacetylases, in mediating downstream tumor suppressive or promoting mechanisms in different cell systems. Although AMPK activation inhibits tumor growth by targeting multiple signaling pathways relevant to tumorigenesis, under certain cellular contexts or certain stages of tumor development, AMPK might act as a protective response to metabolic stresses, such as nutrient deprivation, low oxygen, and low pH, or as downstream effectors of oncogenic proteins, including androgen receptor, hypoxia-inducible factor-1α, c-Src, and MYC. Thus, investigations to define at which stage(s) of tumorigenesis and cancer progression or for which genetic aberrations AMPK inhibition might represent a more relevant strategy than AMPK activation for cancer treatment are clearly warranted.
腺苷单磷酸激活蛋白激酶（AMPK）是应对代谢应激维持能量稳态的关键因子。除了糖尿病和代谢综合征，鉴于AMPK具有通过细胞代谢重编程调节癌细胞增殖的独特能力，人们对其在癌症治疗中的治疗应用兴趣日增。尽管许多研究支持AMPK的肿瘤抑制作用，但新出现的证据表明，AMPK的代谢检查点功能可能会被应激或致癌信号所超越，从而使肿瘤细胞将AMPK激活作为一种生存策略以获得生长优势。这些发现凸显了在生理和病理条件下，AMPK在维持能量稳态的细胞功能中的复杂性。因此，本综述旨在概述AMPK与不同细胞代谢和信号效应器（特别是组蛋白脱乙酰酶）在介导不同细胞系统中下游肿瘤抑制或促进机制方面功能相互作用的最新研究结果。尽管AMPK激活通过靶向与肿瘤发生相关的多个信号通路来抑制肿瘤生长，但在某些细胞环境或肿瘤发展的特定阶段，AMPK可能作为对代谢应激（如营养剥夺、低氧和低pH）的保护反应，或作为致癌蛋白（包括雄激素受体、缺氧诱导因子-1α、c-Src和MYC）的下游效应器。因此，明确确定在肿瘤发生和癌症进展的哪个阶段或针对哪些基因畸变，AMPK抑制可能比AMPK激活更适合作为癌症治疗策略的研究显然是必要的。
