American Association for Cancer Research
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Supplementary Figure 8 from Raf Kinase Inhibitor RKIP Inhibits MDA-9/Syntenin-Mediated Metastasis in Melanoma

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journal contribution
posted on 2023-03-30, 21:09 authored by Swadesh K. Das, Sujit K. Bhutia, Upneet K. Sokhi, Belal Azab, Zhao-zhong Su, Habib Boukerche, Talha Anwar, Erika L. Moen, Devasis Chatterjee, Maurizio Pellecchia, Devanand Sarkar, Paul B. Fisher

PDF file - 180K, Effect of RKIP expression on B-RAF mutant cells



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. Cancer Res; 72(23); 6217–26. ©2012 AACR.

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