Mesenchymal Transition In Prostate Cancer Research Articles

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

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

Abstract C25: Hsp27 is required for EGF-induced epithelial to mesenchymal transition in prostate cancer

Abstract Prostate cancer (PCa) is the most common cancer and the second leading cause cancer death in North American men. Understanding the molecular mechanisms underlying metastatic PCa development is essential to decrease morbidity and mortality. An important determinant for metastasis is epithelial to mesenchymal transition (EMT). We show that the molecular chaperone Hsp27 drives EMT in PCa cells by decreasing epithelial cell markers, upregulating mesenchymal markers and enhancing cell migration and MMP-9 activity. Mechanistically, Hsp27 is required for EMT induced by epidermal growh factor (EGF) via modulation of the beta-catenin/Slug signaling pathway. Hsp27 knockdown induces sequestration of beta-catenin in the cytoplasm by increasing its binding to GSK3beta and abrogating EGF induced beta-catenin nuclear translocation. Additionally, by decreasing the nuclear translocation of beta-catenin, Hsp27 knockdown decreases the binding of beta-catenin to the Slug promoter, thereby abrogating its transcriptional activity. As Slug is known to be a critical factor in EMT induction, we confirmed the role of Hsp27 in EGF mediated EMT using Hsp27 knockdown. To address a role for Hsp27 in promoting aggressive PCa in vivo, Hsp27 was suppressed in a murine model of PCa using the antisense drug OGX-427 (currently in phase II clinical trials). We found OGX-427 treatment significantly reduces tumor cell metastasis in mice, and moreover, decreases circulating tumor cell counts in patients with castration resistant prostate cancer. This study defines a role for Hsp27 as a critical regulator of EGF dependent EMT and highlights Hsp27 is an attractive anti-cancer target for metastatic PCa. Citation Format: Thomas Cordonnier, Jennifer L. Bishop, Masaki Shiota, Ario Takeuchi, Ka Mun Nip, Martin Gleave, Amina Zoubeidi. Hsp27 is required for EGF-induced epithelial to mesenchymal transition in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C25.

Differential Expression of Epithelial and Mesenchymal Proteins in a Panel of Prostate Cancer Cell Lines

Epithelial to mesenchymal transition is an important process that results in increased cell migration, invasion and metastasis of many carcinomas. During epithelial to mesenchymal transition epithelial cells down-regulate cell-cell adhesion molecules (ie E-cadherin), up-regulate mesenchymal proteins (ie N-cadherin and cadherin-11), alter polarity, reorganize the cytoskeleton and become isolated. In combination this leads to greater motility. We investigated the role of E-cadherin and the associated catenin-protein complex in regulating epithelial to mesenchymal transition in prostate cancer progression. The relative invasion index of prostate cancer cells was assessed by MTT based in vitro invasion assay. Immunoprecipitation and Western blot were done to determine cadherin-complex formation, and catenin and cadherin protein expression. Restoration of E-cadherin expression in nonE-cadherin expressing prostate cancer cells decreased invasive potential. However, in vitro invasive potential was tightly regulated by the interaction of cadherin proteins with the catenin complex. E and N-cadherin, cadherin-11, and the catenin proteins α, β, γ and p120 are important for the downstream signaling associated with epithelial to mesenchymal transition in tumor cells. Restoration of epithelial specific proteins, such as E-cadherin, in tumor cells can inhibit invasion. However, invasion is a complex process regulated not only by E and N-cadherin but also by catenin-complex proteins. The complex signaling process associated with tumor invasion warrants further investigation since crosstalk between overlapping signaling pathways is involved in regulating prostate cancer invasion, metastasis and progression.

Epithelial–mesenchymal transition in prostate cancer: providing new targets for therapy

Epithelial–mesenchymal transition in prostate cancer: providing new targets for therapy