Abstract 5194: Induction of Fyn via the Ras/PI3K pathway is necessary and sufficient for enhanced migration and invasion

Abstract

Abstract Over-expression and activation of Src family kinases, particularly Fyn, is relatively frequent in human cancers. Fyn promotes cancer progression, tumor survival and carcinoma invasion, making it a potential molecular target for cancer therapeutics; however the mechanism of Fyn over-expression in cancers is not clear. Since activation of Ras oncogenes in human cancers is a very common oncogenic event, we explored if an active Ras oncogene could induce Fyn expression. Interestingly, retroviral transduction of the immortalized human keratinocyte cell line HaCaT with oncogenic H-Ras dramatically upregulated Fyn mRNA, protein, and activity (>100 fold mRNA induction, p<0.001). Src levels and kinase activity were not affected by H-Ras transduction. Furthermore, activation of Akt, but not MAPK or EGFR, was necessary and sufficient for induction of Fyn by H-Ras. The enhanced migration and invasion induced by H-Ras could be significantly blocked (70% reduction, p<0.0001) by Fyn specific siRNA knockdown or inhibition by PP2 (10 µM). In addition, expression of active Fyn in HaCaT cells was sufficient for increased migration or invasion of cells. These results implicate induction of Fyn in Ras-induced enhanced migration and invasion of cancer cells. Focal adhesion kinase (FAK) activation has been strongly linked with the Ras-mediated increased migratory phenotype of tumor cells. We found that Fyn was necessary and sufficient for Ras induced activation of FAK. In summary, we show that Fyn induction by oncogenic Ras/PI3K/Akt pathway can account for the elevated Src family kinase activity in cancers, and is a critical mediator of the Ras-stimulated invasive cell phenotype. These results have strong implications for the development of therapeutic strategies targeting Akt/Fyn pathway to block migration and invasion of tumor cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5194.