Abstract 1477: Protein Tyrosine Kinase 6 promotes peripheral adhesion complex formation, cell migration, and the epithelial mesenchymal transition in prostate cancer.

Abstract

Abstract Protein tyrosine kinase 6 (PTK6) is an intracellular tyrosine kinase that is evolutionarily related to Src kinases. In the normal prostate, total and active PTK6 is localized within the nucleus, but nuclear localization is lost in prostate tumors. While the majority of total PTK6 is localized within the cytoplasm of PC3 cells, a human prostate cancer cell line, the active pool of PTK6 that is phosphorylated on tyrosine residue 342 is membrane associated. Ectopic expression of membrane targeted PTK6 leads to enhanced activation of PTK6 at the membrane and formation of peripheral adhesion complexes and increased migration of PC3 cells. Ectopic expression of PTK6 in SYF cells, a nontransformed mouse embryonic fibroblast cell line lacking Src, Yes, and Fyn kinases leads to cell transformation and tumor growth in vivo. Ectopic expression of active membrane-targeted PTK6 in PC3 cells promotes the epithelial mesenchymal transition (EMT). PTK6 regulates the EMT through AKT, as knockdown of AKT or inhibition of AKT activity by knockdown of p130CAS partially rescues the phenotype. PC3 cells expressing active membrane targeted PTK6 exhibit increased migration in vitro and form more metastases in a xenograft mouse model, while knockdown of PTK6 promotes an epithelial phenotype and impairs tumorigenesis in vivo. In prostates of Probasin-Cre, Pten flox/flox mice, striking activation of endogenous mouse PTK6 is observed at the membrane in Pten-null prostates, and this is accompanied by deregulated expression of E-cadherin and vimentin. We found a reverse correlation between PTK6 and E-cadherin expression in normal and metastatic human prostate cancer samples, and show PTK6 is activated at the membrane in some high-grade prostate tumors. Our studies reveal novel functions for PTK6 in prostate cancer, and define it as a potential therapeutic target. Citation Format: Angela L. Tyner, Yu Zheng. Protein Tyrosine Kinase 6 promotes peripheral adhesion complex formation, cell migration, and the epithelial mesenchymal transition in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1477. doi:10.1158/1538-7445.AM2013-1477