Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS)
Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS)
复制标题
DOI：
10.1038/sj.onc.1209409
复制
发表时间：
2006-06-22
期刊：
影响因子：
8
通讯作者：
Galeotti, T.
中科院分区：
文献类型：
--
作者：
Ferraro, D.;Corso, S.;Galeotti, T.
C-Met/肝细胞生长因子受体(HGF-R)原癌基因的过度表达和细胞内氧(ROS)的异常产生已被独立的证据与细胞转化和恶性生长联系起来。通过比较具有不同肺转移能力的B16小鼠黑色素瘤的两个亚群(B16-F0和B16-F10)，我们发现c-Met的表达/磷酸化和ROS的稳态水平都与转移生长呈正相关。ShRNA介导的c-Met在F10细胞中的下调导致氧物种的产生和转移能力的平行下降，提示氧化剂可能介导了HGF受体的促转移活性。C-Met被配体激活，通过HGF-R下游的相关靶标--氧化酶偶联的小GTP酶RAC-1诱导氧化剂物种的形成。此外，用催化ROS清除剂EUK-134和EUK-189处理细胞可以减弱Met对ERKs的信号转导，并抑制F10细胞的非锚定生长，这与氧在HGF信号转导和侵略性细胞行为中的关键作用是一致的。最后，在不同水平上对RAC-ROS级联的遗传操作证明了它在体内c-Met促转移活性中的关键作用。因此，我们概述了一个由c-Met触发并由ROS介导的新的级联反应，与转移有关，并可能成为新的抗转移、基于氧化还原的治疗的靶点。
Overexpression of the c-Met/hepatocyte growth factor receptor( HGF-R) proto-oncogene and abnormal generation of intracellular oxygen species ( reactive oxygen species ( ROS)) have been linked, by independent lines of evidence, to cell transformation and to malignant growth. By comparing two subpopulations of the B16 mouse melanoma ( B16-F0 and B16-F10) endowed with different lung metastasis capacities ( low and high, respectively) we found that both the expression/phosphorylation of c-Met and the steady-state levels of ROS positively correlated with metastatic growth. shRNA-mediated downregulation of c-Met in F10 cells led to a parallel decrease in the generation of oxygen species and in metastatic capacity, suggesting that oxidants may mediate the pro-metastatic activity of the HGF receptor. c-Met activation by a ligand elicits the formation of oxidant species through the oxidase-coupled small GTPase Rac-1, a relevant downstream target of the HGF-R. Moreover, cell treatment with the catalytic ROS scavengers EUK-134 and EUK-189 attenuates Met signaling to ERKs and inhibits the anchorage-independent growth of F10 cells, consistent with a critical role for oxygen species in HGF signaling and in aggressive cell behavior. Finally, genetic manipulation of the Rac-ROS cascade at different levels demonstrated its crucial role in the pro-metastatic activity of c- Met in vivo. Thus, we have outlined a novel cascade triggered by c- Met and mediated by ROS, linked to metastasis and potentially targetable by new antimetastatic, redox-based therapies.