Involvement of RHO GTPases and ERK in synuclein-gamma enhanced cancer cell motility.
Synuclein-gamma is aberrantly expressed in more than 70% of stage III/IV breast and ovarian carcinomas. Ectopic overexpression of synuclein-gamma enhanced MDA-MB-435 cell migration in vitro and metastasis in a nude mouse model. However, the mechanism of how synuclein-gamma promotes cell motility is not clear. In our previous studies, we showed that synuclein-gamma overexpression activates ERK. In the present study, we overexpressed synuclein-gamma in several breast and ovarian cancer cell lines and evaluated the effect of synuclein-gamma 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-gamma overexpressing cells. The ERK inhibitor U0126 also blocked the cell migration in both parental cells and synuclein-gamma overexpressing cells. Collectively, our data indicate that synuclein-gamma 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.
Pan
Zhong-Zong
ZZ
Department of Animal Science, University of Vermont, Burlington, VT 05405, USA. zpan@uvm.edu
Bruening
Wendy
W
Godwin
Andrew K
AK
D001426:Bacterial Proteins / Q000494:pharmacology; D001427:Bacterial Toxins / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D009570:Nitriles / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015533:Transcriptional Activation; D014162:Transfection; D051845:gamma-Synuclein / Q000235:genetics / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D002070:Butadienes; D009570:Nitriles; D047428:Protein Kinase Inhibitors; C113580:U 0126; D051845:gamma-Synuclein; C031815:toxB protein, Clostridium difficile; D048049:Extracellular Signal-Regulated MAP Kinases; D020741:rho GTP-Binding Proteins