Involvement of RHO GTPases and ERK in synuclein-γ enhanced cancer cell motility

Abstract

Synuclein-γ is aberrantly expressed in more than 70% of stage III/IV breast and ovarian carcinomas. Ectopic overexpression of synuclein-γ enhanced MDA-MB-435 cell migration in vitro and metastasis in a nude mouse model. However, the mechanism of how synuclein-γ promotes cell motility is not clear. In our previous studies, we showed that synuclein-γ overexpression activates ERK. In the present study, we overexpressed synuclein-γ in several breast and ovarian cancer cell lines and evaluated the effect of synuclein-γ on the activity of small G-protein RHO family members. We found that at least one of the RHO/RAC/CDC42 GTPases showed a higher level of the GTP-bound active form. Consistent with their role in regulating the intracellular motile machinery, inhibition of the RHO/RAC/CDC42 by C. difficile Toxin B blocked cell migration in both parental cells and synuclein-γ overexpressing cells. The ERK inhibitor U0126 also blocked the cell migration in both parental cells and synuclein-γ over-expressing cells. Collectively, our data indicate that synuclein-γ might be involved in late stage breast and ovarian cancer metastasis by enhancing cell motility through activation of the RHO family small-GTPases and ERK.