Abstract 4273: C-kit expression promotes prostate cancer cell migration and invasion through Brca2 downregulation

Abstract

Abstract In many human cancers, expression or activity of the receptor tyrosine kinase (RTK) c-kit is often associated with increased malignancy. In prostate cancer (PCa), we reported an association between expression of c-kit and clinical progression, with the highest expression seen in castrate-resistant metastatic bone specimens. We also found de novo c-kit expression in experimental intraosseous tumors formed by otherwise c-kit negative PCa cells. However, the biological consequences of c-kit expression and activation in PCa cells remain unknown. Here, we show that c-kit overexpression in PC3 and C4-2B PCa cells significantly enhances their migratory and invasive ability in vitro. Consistent with this result, we found that expression and activation of c-kit in PCa cells decreased the expression of E-cadherin and increased the expression of vimentin, suggesting an epithelial mesenchymal transition-like phenomenon. Furthermore, activation by c-kit ligand in PC3 and C4-2B cells transfected with c-kit lead to phosphorylation of Akt. This contributes to the enhanced invasiveness of c-kit-expressing PCa cells, as demonstrated by an inhibitory effect by PI3K/Akt inhibitors LY294002 and Wortmannin. In an attempt to identify genes differentially expressed in c-kit-expressing and -non-expressing PCa cells, we used a microarray containing 84 genes, representing growth factor receptors, transcription factors, cell cycle, and DNA repair genes. The analysis of the array demonstrated a consistent down-regulation of Brca2 in both c-kit-expressing PC3 and C4-2B cells, further validated by qRT-PCR and immunoblotting. Re-introduction of Brca2 into c-kit-expressing PCa cells suppressed c-kit-enhanced invasiveness to levels similar to those shown by c-kit-non-expressing cells, and led to reduced phosphorylation of Akt. Our results provide evidence that c-kit expression in PCa cells, an event which is induced upon interaction with the bone microenvironment, promotes tumor migration and invasion through an Akt-dependent mechanism regulated by Brca2 down-regulation. The identification of this novel signaling axis and its importance in PCa migration and invasion reveal potential therapeutic targets for regulating the expansion of PCa metastatic lesions in bone. 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 4273. doi:1538-7445.AM2012-4273