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

D. Ferraro, S. Corso, E. Fasano, E. Panieri, R. Santangelo, S. Borrello, S. Giordano, G. Pani, T. Galeotti

Research output: Contribution to journalArticle

94 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3689-3698
Number of pages10
JournalOncogene
Volume25
Issue number26
DOIs
Publication statusPublished - Jun 22 2006

Fingerprint

Reactive Oxygen Species
Proto-Oncogene Proteins c-met
Oxygen
Oxidants
Growth
Neoplasm Metastasis
Lung Volume Measurements
Experimental Melanomas
Monomeric GTP-Binding Proteins
Proto-Oncogenes
Small Interfering RNA
Oxidation-Reduction
Oxidoreductases
Down-Regulation
Phosphorylation
Ligands
Therapeutics

Keywords

  • c-Met
  • Metastasis
  • Rac-1
  • Reactive oxygen species
  • Signal transduction

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Ferraro, D., Corso, S., Fasano, E., Panieri, E., Santangelo, R., Borrello, S., ... Galeotti, T. (2006). Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS). Oncogene, 25(26), 3689-3698. https://doi.org/10.1038/sj.onc.1209409

Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS). / Ferraro, D.; Corso, S.; Fasano, E.; Panieri, E.; Santangelo, R.; Borrello, S.; Giordano, S.; Pani, G.; Galeotti, T.

In: Oncogene, Vol. 25, No. 26, 22.06.2006, p. 3689-3698.

Research output: Contribution to journalArticle

Ferraro, D, Corso, S, Fasano, E, Panieri, E, Santangelo, R, Borrello, S, Giordano, S, Pani, G & Galeotti, T 2006, 'Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS)', Oncogene, vol. 25, no. 26, pp. 3689-3698. https://doi.org/10.1038/sj.onc.1209409
Ferraro D, Corso S, Fasano E, Panieri E, Santangelo R, Borrello S et al. Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS). Oncogene. 2006 Jun 22;25(26):3689-3698. https://doi.org/10.1038/sj.onc.1209409
Ferraro, D. ; Corso, S. ; Fasano, E. ; Panieri, E. ; Santangelo, R. ; Borrello, S. ; Giordano, S. ; Pani, G. ; Galeotti, T. / Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS). In: Oncogene. 2006 ; Vol. 25, No. 26. pp. 3689-3698.
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