Abstract 1055: Syntenin positively regulates TGF-β1- and oncogenic Ras-mediated EMT-like phenotypic changes in cancer cells

Abstract

Abstract Epithelial to mesenchymal transition (EMT) is biological process in polarized epithelial cells, which occurs in various physiological and pathological conditions. In carcinoma progression, EMT has emerged as a critical player in regulating cancer cell invasive phenotype. Syntenin, a tandem PDZ-domain containing scaffold protein, functions as a positive regulator of cancer cell progression in several human cancers. In present study, we investigated a role of syntenin in transforming growth factor (TGF)-β1- and Ras-V12-mediated EMT-like phenotypic changes in cancer cells. Knockdown of syntenin suppressed TGF-β1- and Ras-V12-induced morphological and cell biological alterations in A549, Ep/Ras, and BEAS-2B cells that are consistent with EMT; however, overexpression of syntenin stimulated TGF-β1- and Ras-V12-induced EMT, implying that syntenin is necessary for TGF-β1- and Ras-V12- induced EMT. We found that syntenin is associated with RSK (p90 ribosomal S6 kinase) via PDZ binding motif and syntenin at Ser6 residue may directly be phosphorylated by RSK. Mutation of syntenin Ser6 to Ala suppresses TGF-β1- and oncogenic Ras-mediated EMT in a dominant negative manner by abolishing the interaction of endogenous syntenin with RSK. Strikingly, expression of syntenin-S6E, a phosphomimetic mutant of syntenin at Ser6, into A549, Ep/Ras, or BEAS-2B cells induced EMT-like phenotypic changes, characterized by down-regulation of E-cadherin and up-regulation of vimentin, Snail and Slug, suggesting that Ser6 phosphorylation of syntenin by RSK is necessary and sufficient for the induction of EMT mediated by TGF-β1. In addition, we sought to determine whether Ser6 phosphorylation of syntenin would modulate in vivo metastasis in a mouse model. A549 cells expressing syntenin-S6E dramatically increased lung metastases. Based on these data, we conclude that phosphorylation of syntenin at Ser6 by RSK is necessary and sufficient for the induction of EMT and metastasis in certain cancer cells. Citation Format: Okhwa Kim, Cheol Hwangbo, Nara Tae, Suhyun Lee, Jeong-Hyung Lee. Syntenin positively regulates TGF-β1- and oncogenic Ras-mediated EMT-like phenotypic changes in cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1055. doi:10.1158/1538-7445.AM2014-1055