Raf kinase inhibitor RKIP inhibits MDA-9/syntenin-mediated metastasis in melanoma.
Cancer Res
; 72(23): 6217-26, 2012 Dec 01.
Article
in En
| MEDLINE
| ID: mdl-23066033
ABSTRACT
Melanoma differentiation associated gene-9 (MDA-9), also known as syntenin, functions as a positive regulator of melanoma progression and metastasis. In contrast, the Raf kinase inhibitor, RKIP, a negative modulator of RAF-stimulated MEKK activation, is strongly downregulated in metastatic melanoma cells. In this study, we explored a hypothesized inverse relationship between MDA-9 and RKIP in melanoma. Tumor array and cell line analyses confirmed an inverse relationship between expression of MDA-9 and RKIP during melanoma progression. We found that MDA-9 transcriptionally downregulated RKIP in support of a suggested cross-talk between these two proteins. Furthermore, MDA-9 and RKIP physically interacted in a manner that correlated with a suppression of FAK and c-Src phosphorylation, crucial steps necessary for MDA-9 to promote FAK/c-Src complex formation and initiate signaling cascades that drive the MDA-9-mediated metastatic phenotype. Finally, ectopic RKIP expression in melanoma cells overrode MDA-9-mediated signaling, inhibiting cell invasion, anchorage-independent growth, and in vivo dissemination of tumor cells. Taken together, these findings establish RKIP as an inhibitor of MDA-9-dependent melanoma metastasis, with potential implications for targeting this process therapeutically.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Raf Kinases
/
Phosphatidylethanolamine Binding Protein
/
Syntenins
/
Melanoma
Limits:
Animals
/
Humans
Language:
En
Journal:
Cancer Res
Year:
2012
Document type:
Article
Affiliation country:
United States