Abstract 3254: Cadherin-11 function is required for full neoplastic transformation by v-Src

Abstract

Abstract The signal transducer and activator of transcription-3 (Stat3) has emerged as an important signal transducer with a role in cancer etiology. Following activation of a number of growth factor or cytokine receptors or expression of oncogenes such as vSrc, Stat3 is phosphorylated at tyr-705, dimerizes and migrates to the nucleus where it activates transcription from a number of genes involved in cell division and survival. We recently discovered a novel pathway of activation of Stat3, triggered by cadherin engagement. Stat3 activation was caused by a striking upregulation of the Rac GTPase and IL6, and induced downregulation of the p53 antioncogene, upregulation of anti-apoptotic genes and a potent survival signal. A large number of oncogenes such as vSrc activate the E2F transcription factor, found to be hyperactive in many cancers. E2F induces the expression of genes involved in cell division, as well as a number of receptor tyrosine kinases, that can, in turn, activate Stat3. However, at the same time E2F is a potent apoptosis inducer, hence the high demand of transformed cells for survival signals. Since cadherin engagement activates Stat3, a potent survival signal, we examined the effect of downregulation of cadherin-11 upon transformation of mouse Balb/c3T3 fibroblasts by vSrc. Cadherin-11 knockdown through shRNA expression with a retroviral vector caused a dramatic reduction in Stat3 activity. At the same time, expression of vSrc in cadherin-11 knockdown cells failed to cause transformation; in the contrary, vSrc expression induced apoptosis. These data indicate that cadherin-11 is necessary for full neoplastic transformation of mouse fibroblasts by vSrc. This is especially remarkable because Src has been shown to have a negative effect upon, although not eliminate cadherin function, since Stat3 activity was, in fact increased in vSrc-expressing cells upon cadherin engagement. Therefore, it appears that the residual amounts of cadherin-11 present are sufficient to activate Stat3 and prevent apoptosis induced by the Src/E2F axis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3254. doi:1538-7445.AM2012-3254