Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, 610064 Chengdu, China.
Department of Radiology, Sichuan Cancer Hospital, 610041 Chengdu, China.
Proc Natl Acad Sci U S A. 2020 Apr 7;117(14):8013-8021. doi: 10.1073/pnas.1914786117. Epub 2020 Mar 19.
AMP-activated protein kinase (AMPK) functions as an energy sensor and is pivotal in maintaining cellular metabolic homeostasis. Numerous studies have shown that down-regulation of AMPK kinase activity or protein stability not only lead to abnormality of metabolism but also contribute to tumor development. However, whether transcription regulation of AMPK plays a critical role in cancer metastasis remains unknown. In this study, we demonstrate that AMPKα1 expression is down-regulated in advanced human breast cancer and is associated with poor clinical outcomes. Transcription of AMPKα1 is inhibited on activation of PI3K and HER2 through ΔNp63α. Ablation of AMPKα1 expression or inhibition of AMPK kinase activity leads to disruption of E-cadherin-mediated cell-cell adhesion in vitro and increased tumor metastasis in vivo. Furthermore, restoration of AMPKα1 expression significantly rescues PI3K/HER2-induced disruption of cell-cell adhesion, cell invasion, and cancer metastasis. Together, these results demonstrate that the transcription control is another layer of AMPK regulation and suggest a critical role for AMPK in regulating cell-cell adhesion and cancer metastasis.
AMP 激活的蛋白激酶 (AMPK) 作为能量传感器发挥作用，对于维持细胞代谢稳态至关重要。大量研究表明，AMPK 激酶活性或蛋白稳定性的下调不仅导致代谢异常，而且还促进肿瘤的发展。然而，AMPK 的转录调控是否在癌症转移中起关键作用尚不清楚。在这项研究中，我们证明 AMPKα1 的表达在晚期人乳腺癌中下调，并与不良的临床结局相关。AMPKα1 的转录在 PI3K 和 HER2 的激活下通过 ΔNp63α 受到抑制。AMPKα1 表达的缺失或 AMPK 激酶活性的抑制导致体外 E-钙黏蛋白介导的细胞间黏附破坏，并增加体内肿瘤转移。此外，AMPKα1 表达的恢复显著挽救了 PI3K/HER2 诱导的细胞间黏附、细胞侵袭和癌症转移的破坏。总之，这些结果表明转录控制是 AMPK 调节的另一层，提示 AMPK 在调节细胞间黏附和癌症转移中起关键作用。
