Raf kinase inhibitor RKIP inhibits MDA-9/syntenin-mediated metastasis in melanoma.
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.
Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
Swadesh K
SK
Das
Sujit K
SK
Bhutia
Upneet K
UK
Sokhi
Belal
B
Azab
Zhao-Zhong
ZZ
Su
Habib
H
Boukerche
Talha
T
Anwar
Erika L
EL
Moen
Devasis
D
Chatterjee
Maurizio
M
Pellecchia
Devanand
D
Sarkar
Paul B
PB
Fisher
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D002642:Chick Embryo; D015536:Down-Regulation; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D049488:Phosphatidylethanolamine Binding Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053676:Syntenins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D048490:raf Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D016328:NF-kappa B; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D012333:RNA, Messenger; C109621:SDCBP protein, human; D053676:Syntenins; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D048490:raf Kinases