Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Pathology, Chi-Mei Medical Center, Tainan 710, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan; Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
Mol Cell. 2020 Oct 15;80(2):263-278.e7. doi: 10.1016/j.molcel.2020.09.018. Epub 2020 Oct 5.
Cancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. This AMPK-PDHc axis is activated in advanced breast cancer and predicts poor metastasis-free survival. Mechanistically, AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. Importantly, these phosphorylation events mediate PDHc function in cancer metastasis. Our study reveals that AMPK-mediated PDHA phosphorylation drives PDHc activation and TCA cycle to empower cancer cells adaptation to metastatic microenvironments for metastasis.
癌症转移是癌症相关死亡的主要原因。播散的癌细胞如何应对次级部位的恶劣微环境，从而全面转移，在很大程度上尚不清楚。在这里，我们表明，在小鼠转移模型中被激活的 AMPK（AMP 激活的蛋白激酶）驱动丙酮酸脱氢酶复合物（PDHc）的激活，以维持三羧酸循环（TCA 循环），并通过使癌细胞适应代谢和氧化应激来促进癌症转移。该 AMPK-PDHc 轴在晚期乳腺癌中被激活，并预测无转移生存不良。从机制上讲，AMPK 定位于线粒体基质中，并在线粒体基质中磷酸化 PDHc 的催化α亚基（PDHA）上的两个残基 S295 和 S314，分别激活 PDHc 的酶活性并减轻 PDHKs 的抑制性磷酸化。重要的是，这些磷酸化事件介导了 PDHc 在癌症转移中的功能。我们的研究表明，AMPK 介导的 PDHA 磷酸化驱动 PDHc 激活和 TCA 循环，使癌细胞能够适应转移微环境进行转移。
