Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, Karnataka, India.
Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, Karnataka, India
J Cell Sci. 2018 Jul 26;131(14):jcs208314. doi: 10.1242/jcs.208314.
The developmental programme of epithelial-mesenchymal transition (EMT), involving loss of epithelial and acquisition of mesenchymal properties, plays an important role in the invasion-metastasis cascade of cancer cells. In the present study, we show that activation of AMP-activated protein kinase (AMPK) using A769662 led to a concomitant induction of EMT in multiple cancer cell types, as observed by enhanced expression of mesenchymal markers, decrease in epithelial markers, and increase in migration and invasion. In contrast, inhibition or depletion of AMPK led to a reversal of EMT. Importantly, AMPK activity was found to be necessary for the induction of EMT by physiological cues such as hypoxia and TGFβ treatment. Furthermore, AMPK activation increased the expression and nuclear localization of Twist1, an EMT transcription factor. Depletion of Twist1 impaired AMPK-induced EMT phenotypes, suggesting that AMPK might mediate its effects on EMT, at least in part, through Twist1 upregulation. Inhibition or depletion of AMPK also attenuated metastasis. Thus, our data underscore a central role for AMPK in the induction of EMT and in metastasis, suggesting that strategies targeting AMPK might provide novel approaches to curb cancer spread.
上皮-间质转化（EMT）的发育程序涉及上皮细胞的丧失和间充质特性的获得，在癌细胞的侵袭-转移级联中起着重要作用。在本研究中，我们表明，使用 A769662 激活 AMP 激活蛋白激酶（AMPK）会导致多种癌细胞类型同时发生 EMT，表现为间充质标志物表达增强、上皮标志物减少以及迁移和侵袭增加。相比之下，抑制或耗尽 AMPK 会导致 EMT 逆转。重要的是，发现 AMPK 活性对于缺氧和 TGFβ 处理等生理信号诱导 EMT 是必需的。此外，AMPK 激活增加了 EMT 转录因子 Twist1 的表达和核定位。Twist1 的耗竭削弱了 AMPK 诱导的 EMT 表型，表明 AMPK 可能通过 Twist1 的上调来介导其对 EMT 的影响，至少部分如此。抑制或耗尽 AMPK 也会减弱转移。因此，我们的数据强调了 AMPK 在诱导 EMT 和转移中的核心作用，表明靶向 AMPK 的策略可能为抑制癌症扩散提供新的方法。
