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  • Original Article
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Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS)

Abstract

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.

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Abbreviations

HGF-R:

hepatocyte growth factor receptor

ROS:

reactive oxygen species

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Acknowledgements

We thank Drs Paola Chiarugi, Toren Finkel, John Collard and Alan Hall for important reagents, Dr Caterina Capone for experimental contribution and all the members of the laboratory for helpful discussions. The present work was cofunded by the Italian Ministry for Education and Scientific Research (MIUR) (Grant no. 2004054004-003 to TG), and the Catholic University Medical School (grants ‘ex 60%’ to GP, TG and SB).

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Correspondence to G Pani.

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Ferraro, D., Corso, S., Fasano, E. et al. Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS). Oncogene 25, 3689–3698 (2006). https://doi.org/10.1038/sj.onc.1209409

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