Integrin-Regulated Kinase PYK-2: A Therapeutic Target for Prostate Cancer.

摘要

A prostate cancer cell's growth, differentiation and survival are guided by its interactions with the surrounding extracellular matrix (ECM) . A number of promising therapeutic targets for androgen-independent and metastatic prostate cancers are contained within the signaling cascades downstream of the ECM-binding Integrin molecules. My research focuses on one component of these cascades, the phospho-tyrosine kinase PYK-2, whose expression levels and activity I aim to manipulate in cell culture and within tumors in mice. This past year, after redirecting my research approach somewhat because of technical difficulties, I can now report that I have: (1) characterized PYK-2 expression in prostate tissues and cell lines; (2) linked Green Fluorescent Protein (GFP) to both PYK- 2 and dominant-negative PYK-2 (PRNK), transiently transfected cells with these constructs, and studied protein localization and construct effects on cell growth, apoptosis and migratory behaviors; (3) quantified integrin subunit expression levels in cell lines of different metastatic potential and assayed the tyrosine phosphorylation states of endogenous PYK-2, following cell adhesion to different ECM substrata; (4) generated a virus expression vector with a tissue-specific promotor that will be used for in vivo animal experiments; and finally (5) begun microarray analysis of gene expression changes accompanying shifts in the levels of PYK-2 and PRNK. The work is ongoing and will continue in my new position at Emory University.