Zhao Hong, Orhan Yelda C, Zha Xiaoming, Esencan Ecem, Chatterton Robert T, Bulun Serdar E
Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University Chicago, IL, USA.
Department of Surgery, The First Affiliated Hospital of Nanjing Medical School Nanjing, Jiangsu, China.
Am J Transl Res. 2017 Feb 15;9(2):197-213. eCollection 2017.
Cancer growth and metastasis depends on the availability of energy. Energy-sensing systems are critical in maintaining a balance between the energy supply and utilization of energy for tumor growth. A central regulator in this process is AMP-activated protein kinase (AMPK). In times of energy deficit, AMPK is allosterically modified by the binding of increased levels of AMP and ADP, making it a target of specific AMPK kinases (AMPKKs). AMPK signaling prompts cells to produce energy at the expense of growth and motility, opposing the actions of insulin and growth factors. Increasing AMPK activity may thus prevent the proliferation and metastasis of tumor cells. Activated AMPK also suppresses aromatase, which lowers estrogen formation and prevents breast cancer growth. Biguanides can be used to activate AMPK, but AMPK activity is modified by many different interacting factors; understanding these factors is important in order to control the abnormal growth processes that lead to breast cancer neoplasia. Fatty acids, estrogens, androgens, adipokines, and another energy sensor, sirtuin-1, alter the phosphorylation and activation of AMPK. Isoforms of AMPK differ among tissues and may serve specific functions. Targeting AMPK regulatory processes at points other than the upstream AMPKKs may provide additional approaches for prevention of breast cancer neoplasia, growth, and metastasis.
癌症的生长和转移依赖于能量的供应。能量传感系统对于维持肿瘤生长的能量供应与利用之间的平衡至关重要。这一过程中的核心调节因子是AMP激活的蛋白激酶（AMPK）。在能量不足时，AMPK会通过与水平升高的AMP和ADP结合而发生别构修饰，使其成为特定AMPK激酶（AMPKKs）的作用靶点。AMPK信号传导促使细胞以牺牲生长和运动能力为代价来产生能量，这与胰岛素和生长因子的作用相反。因此，增加AMPK活性可能会阻止肿瘤细胞的增殖和转移。激活的AMPK还会抑制芳香化酶，从而降低雌激素的生成并阻止乳腺癌的生长。双胍类药物可用于激活AMPK，但AMPK的活性会受到许多不同相互作用因子的影响；了解这些因子对于控制导致乳腺癌形成的异常生长过程至关重要。脂肪酸、雌激素、雄激素、脂肪因子以及另一种能量传感器——沉默调节蛋白1，都会改变AMPK的磷酸化和激活状态。AMPK的亚型在不同组织中存在差异，可能具有特定功能。针对上游AMPKKs以外的其他位点靶向AMPK调节过程，可能为预防乳腺癌形成及其生长和转移提供额外的方法。
