Regulation of the Epithelial-Mesenchymal Transition in Prostate Cancer

Abstract

Abstract : Protein tyrosine kinase 6 (PTK6) is a nonmyristoylated intracellular tyrosine kinase that is expressed in the normal prostate and in prostate cancers. We had hypothesized that PTK6 regulates the activities of its nuclear substrate, the KH domain RNAbinding protein SAM68, to control the epithelial mesenchymal transition (EMT) in prostate cancer. However, during the course of our studies, we determined that PTK6 membrane-associated functions, not nuclear functions, regulate the EMT. We found that while most PTK6 protein is located within the cytoplasm, the pool of active PTK6 is membrane-associated in prostate cancer cells. We showed that membrane-targeted activated PTK6 induces formation of peripheral adhesion complexes accompanied by decreased E-cadherin expression and increased expression of mesenchymal markers, hallmarks of the EMT. Membrane-targeted active PTK6 promoted the epithelial mesenchymal transition in prostate cancer cells, partially through enhancing AKT activation, and increasing anchorage independent growth and cell migration. Our analysis of Oncomine data indicated that high levels of PTK6 predict poor prognosis for prostate cancer patients. Our findings identify PTK6 as a new candidate therapeutic target in metastatic prostate cancer.