PROTEIN KINASE C EPSILON COOPERATES WITH PTEN LOSS FOR PROSTATE TUMORIGENESIS THROUGH THE CXCL13-CXCR5 PATHWAY. Mus musculus

PKCe, an oncogenic member of the PKC family, is aberrantly overexpressed in epithelial cancers. To date, little is known about functional interactions of PKCe with other genetic alterations and the effectors of this kinase that contribute to its tumorigenic and metastatic phenotype. Here we demonstrate that PKCe cooperates with the loss of the tumor suppressor Pten for the development of prostate cancer in a mouse model. Mechanistic analysis revealed that PKCe overexpression and Pten loss individually and synergically cause a remarkable up-regulation in the production of the chemokine CXCL13. Notably, targeted disruption of CXCL13 or its receptor CXCR5 in prostate cancer cells impaired their migratory and tumorigenic properties. In addition to providing evidence for an autonomous vicious cycle driven by PKCe, our studies identified a compelling rationale for targeting the CXCL13:CXCR5 axis for prostate cancer treatment. Overall design: Affymetrix based gene expression profiles of 4 murine prostate epithelial cell lines (P8, CaP8, P8-PKCε and CaP8-PKCε) were generated (3 replicates in each case).