Prostate cancer is the second leading cause of cancer-related deaths among men in the US. A large body of evidence links protein kinase C epsilon (PKC?) to cancer progression. PKC? is markedly up-regulated in epithelial cancers, including prostate cancer, potentially reflecting its involvement in the etiology and progression o the disease. We found that prostate-specific PKC? transgenic mice (PB-PKC?) develop preneoplastic lesions (PINs), and remarkably, they develop invasive prostatic adenocarcinomas in a Pten haplodeficient background. Understanding the molecular basis of this cooperativity is highly relevant, as loss of the tumor suppressor Pten, a negative regulator of the PI3K pathway, is a common alteration of prostate cancer. We generated a number of cellular models recapitulating PKC? overexpression and Pten loss, which display enhanced growth, motility, and invasiveness in vitro, and acquire tumorigenic potential in nude mice. Moreover, gene profiling and bioinformatics analysis revealed that PKC? overexpressing/Pten depleted cells display a pattern of gene expression distinctive of human metastatic prostate cancer. We found that the top hit in this microarray analysis is the chemokine CXCL13. Notably, PKC? cooperates with Pten loss to strongly induce CXCL13 mRNA levels and its release, and RNAi depletion of CXCL13 or its receptor (CXCR5) impairs the ability of PKC? overexpressing/Pten-deficient cells to proliferate and migrate. Preliminary data also suggest that PKC? and PI3K are downstream effectors of CXCR5, suggesting a positive amplification loop that may act as a vicious cycle.
In Specific Aim 1, we will establish the relevance of the CXCL13:CXCR5 axis in prostate tumorigenesis using an inducible silencing approach. A potential contribution of stromal CXCL13 will be examined using immunocompetent mice and depletion of lymphocytes involved in CXCL13 production. In addition, knock-out CXCL13 and CXCR5 mice will be crossed with PB- PKC? mice as an approach to assess the requirement of the CXCL13:CXCR5 axis in the development of prostate lesions and the activation of key mitogenic/survival pathways.
In Specific Aim 2, we will examine the role of CXCL13:CXCR5 in metastasis using intraprostatic injections and also assess the role of this pathway in metastatic dissemination to bone. Mechanistic studies will be pursued to explore the potential relevance of Rac, a small G-protein, and its exchange factors (Rac-GEFs) in the motile/invasive phenotype driven by the PKC?-PI3K-CXCL13-CXCR5 pathway.
In Specific Aim 3, we will focus on the mechanisms involved in CXCL13 induction by PKC? and PI3K, specifically dissecting the roles of Akt, Erk, Stat3, NF-?B and specific p110 PI3Ks in controlling CXCL13 production. We will also investigate PKC? as a potential CXCR5 downstream effector. Lastly, in Specific Aim 4 we will establish the relevance of the PKC?/Pten-CXCL13 association in human prostate tumors using a large collection of prostate cancer specimens, and assess correlations with disease progression and recurrence. In addition to the mechanistic implications, the proposed studies may have major prognostic and therapeutic impact for personalized prostate cancer treatment.

Public Health Relevance

In this application we will investigate a paradigm recently identified in our laboratory that has not been previously appreciated in prostate cancer or other cancers, and has remarkable translational potential. Specifically, we identified the chemokine CXCL13 and its receptor CXCR5 as key mediators of oncogenic inputs known to drive tumorigenesis and metastasis of prostate cancer cells. We will investigate how the CXCL13:CXCR5 pathway mediates the oncogenic activity of protein kinase C epsilon (PKC?) and its functional interaction with the PI3K pathway, particularly the loss of the tumor suppressor Pten. Our proposal encompasses mechanistic, cellular, and animal studies, as well as expression analysis in human prostate cancer specimens. Our studies may have significant implications for the understanding of prostate cancer etiology as well as great potential at prognostic and therapeutic levels.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Ault, Grace S
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University of Pennsylvania
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Casado-Medrano, Victoria; Baker, Martin J; Lopez-Haber, Cynthia et al. (2018) The role of Rac in tumor susceptibility and disease progression: from biochemistry to the clinic. Biochem Soc Trans 46:1003-1012
Garg, Rachana; Blando, Jorge M; Perez, Carlos J et al. (2018) COX-2 mediates pro-tumorigenic effects of PKC? in prostate cancer. Oncogene 37:4735-4749
Cooke, Mariana; Zhou, Xiaoling; Casado-Medrano, Victoria et al. (2018) Characterization of AJH-836, a diacylglycerol-lactone with selectivity for novel PKC isozymes. J Biol Chem 293:8330-8341
Garg, Rachana; Blando, Jorge M; Perez, Carlos J et al. (2017) Protein Kinase C Epsilon Cooperates with PTEN Loss for Prostate Tumorigenesis through the CXCL13-CXCR5 Pathway. Cell Rep 19:375-388
Cooke, Mariana; Magimaidas, Andrew; Casado-Medrano, Victoria et al. (2017) Protein kinase C in cancer: The top five unanswered questions. Mol Carcinog 56:1531-1542
Kazanietz, Marcelo G; Caloca, Maria J (2017) The Rac GTPase in Cancer: From Old Concepts to New Paradigms. Cancer Res 77:5445-5451