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.

HIF-1α stabilization by mitochondrial ROS promotes Met-dependent invasive growth and vasculogenic mimicry in melanoma cells

“…Rac1b, a differentially spliced form of Rac1, has been reported to generate carcinogenic ROS during metalloproteaseinduced EMT of mammary epithelial cells [42]. In keeping with this, Rac1-mediated redox signaling has been reported as vital for melanoma aggressiveness upon expression and activation of Met, a known regulator of the EMT [32,43]. Hypoxia has already been correlated with EMT and the consequent acquisition of a motile/invasive behavior [44].…”

Mitochondrial pyrimidine nucleotide carrier (PNC1) regulates mitochondrial biogenesis and the invasive phenotype of cancer cells

“…However, damaged mitochondria may also directly participate in increasing metastatic potential by activating a reactive oxygen species (ROS)-mediated retrograde signalling pathway (Ferraro et al, 2006;Owusu-Ansah et al, 2008). Earlier studies have correlated elevated levels of ROS in cancer cells with carcinogenesis (Klaunig et al, 1998;Mori et al, 2004).…”

Oxidative Therapy Against Cancer

“…On the other hand, greater metastatic capacity has been associated with high ROS levels in most tumors (Ishikawa et al, 2008). So, exogenous administration of ROS could increase certain metastatic states, while a treatment with antioxidants could slow down the metastatic progression (Ferraro et al, 2006).…”