Ouabain impairs cancer metabolism and activates AMPK-Src signaling pathway in human cancer cell lines
Ouabain impairs cancer metabolism and activates AMPK-Src signaling pathway in human cancer cell lines
复制标题
哇巴因损害人类癌细胞系中的癌症代谢并激活 AMPK-Src 信号通路
DOI：
10.1038/s41401-019-0290-0
复制
发表时间：
2020-01-01
影响因子：
8.2
通讯作者：
Wang, Zhen
中科院分区：
文献类型：
--
作者：
Shen, Jia-jia;Zhan, Yue-chen;Wang, Zhen
除了众所周知的强心作用外，强心苷（CG）还通过各种分子机制产生有效的抗癌作用。我们以前表明，哇巴因诱导自噬细胞死亡的人肺癌细胞通过调节AMPK介导的mTOR和Src介导的ERK 1/2信号通路。然而，AMPK和Src信号是否以及如何在哇巴因处理的癌细胞中相互作用仍不清楚。鉴于AMPK在代谢中的关键作用，哇巴因是否会影响癌细胞的代谢仍然是难以捉摸的。在这项研究中，我们发现，哇巴因（25 nM）治疗引起的AMPK和Src信号通路在人肺癌A549细胞和人乳腺癌MCF 7细胞的同时激活。与AMPK抑制剂化合物C或siRNA的共处理极大地消除了哇巴因诱导的Src激活，而与Src抑制剂PP 2的共处理对哇巴因诱导的AMPK活性几乎没有影响，这表明AMPK作为Src信号通路的上游调节剂。另一方面，哇巴因处理极大地消耗A549和MCF 7细胞中的ATP产生，并且补充ATP（100 μM）阻断哇巴因诱导的AMPK活化。我们进一步证明，哇巴因大大抑制癌细胞中的线粒体氧化磷酸化（OXPHOS），并根据癌细胞类型对糖酵解产生不同的代谢作用。总之，这项研究表明，哇巴因引起的癌细胞代谢的改变可能有助于AMPK活化，以及其对癌细胞的细胞毒性。
In addition to the well-known cardiotonic effects, cardiac glycosides (CGs) produce potent anticancer effects with various molecular mechanisms. We previously show that ouabain induces autophagic cell death in human lung cancer cells by regulating AMPK-mediated mTOR and Src-mediated ERK1/2 signaling pathways. However, whether and how AMPK and Src signaling interacts in ouabain-treated cancer cells remains unclear. Given the pivotal role of AMPK in metabolism, whether ouabain affects cancer cell metabolism remains elusive. In this study we showed that treatment with ouabain (25 nM) caused simultaneous activation of AMPK and Src signaling pathways in human lung cancer A549 cells and human breast cancer MCF7 cells. Cotreatment with AMPK inhibitor compound C or siRNA greatly abrogates ouabain-induced Src activation, whereas cotreatment with Src inhibitor PP2 has little effect on ouabain-induced AMPK activity, suggesting that AMPK served as an upstream regulator of the Src signaling pathway. On the other hand, ouabain treatment greatly depletes ATP production in A549 and MCF7 cells, and supplement of ATP (100 μM) blocked ouabain-induced AMPK activation. We further demonstrated that ouabain greatly inhibited the mitochondrial oxidative phosphorylation (OXPHOS) in the cancer cells, and exerted differential metabolic effects on glycolysis depending on cancer cell type. Taken together, this study reveals that the altered cancer cell metabolism caused by ouabain may contribute to AMPK activation, as well as its cytotoxicity towards cancer cells.