title: Protein Kinase C Epsilon Cooperates with PTEN Loss for Prostate Tumorigenesis through the CXCL13-CXCR5 Pathway.
abstract: PKCε, an oncogenic member of the PKC family, is aberrantly overexpressed in epithelial cancers. To date, little is known about functional interactions of PKCε with other genetic alterations, as well as the effectors contributing to its tumorigenic and metastatic phenotype. Here, we demonstrate that PKCε cooperates with the loss of the tumor suppressor Pten for the development of prostate cancer in a mouse model. Mechanistic analysis revealed that PKCε overexpression and Pten loss individually and synergistically upregulate the production of the chemokine CXCL13, which involves the transcriptional activation of the CXCL13 gene via the non-canonical nuclear factor κB (NF-κB) pathway. 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 PKCε, our studies identified a compelling rationale for targeting the CXCL13-CXCR5 axis for prostate cancer treatment.
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Rachana
authors.initials: R
authors.lastname: Garg
authors.affiliation: Immunopathology Laboratory, Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jorge M
authors.initials: JM
authors.lastname: Blando
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Perez
authors.affiliation: Centro de Investigaciones Inmunológicas Básicas y Aplicadas-CONICET, Universidad Nacional de La Plata, CP1900 La Plata, Argentina.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Abba
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Benavides
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: marcelog@upenn.edu.
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Kazanietz
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D054382:Chemokine CXCL13 / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D016328:NF-kappa B; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis* / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D051744:Protein Kinase C-epsilon / Q000096:biosynthesis* / Q000235:genetics; D054380:Receptors, CXCR5 / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C110663:CXCL13 protein, human; C095085:CXCR5 protein, human; D054382:Chemokine CXCL13; D016328:NF-kappa B; D054380:Receptors, CXCR5; D051744:Protein Kinase C-epsilon; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: CXCL13; CXCR5; NF-κB; PKCε; PTEN; migration; proliferation; prostate cancer; transgenic mice