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 language | English |
|---|---|
| Pages (from-to) | 3689-3698 |
| Number of pages | 10 |
| Journal | Oncogene |
| Volume | 25 |
| Issue number | 26 |
| DOIs | |
| Publication status | Published - Jun 22 2006 |
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Keywords
- c-Met
- Metastasis
- Rac-1
- Reactive oxygen species
- Signal transduction
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Genetics
Cite this
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 journal › Article
}
TY - JOUR
T1 - Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS)
AU - Ferraro, D.
AU - Corso, S.
AU - Fasano, E.
AU - Panieri, E.
AU - Santangelo, R.
AU - Borrello, S.
AU - Giordano, S.
AU - Pani, G.
AU - Galeotti, T.
PY - 2006/6/22
Y1 - 2006/6/22
N2 - 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.
AB - 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.
KW - c-Met
KW - Metastasis
KW - Rac-1
KW - Reactive oxygen species
KW - Signal transduction
UR - http://www.scopus.com/inward/record.url?scp=33745534837&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33745534837&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1209409
DO - 10.1038/sj.onc.1209409
M3 - Article
VL - 25
SP - 3689
EP - 3698
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 26
ER -