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Protein Kinase C Epsilon Cooperates with PTEN Loss for Prostate Tumorigenesis through the CXCL13-CXCR5 Pathway
Rachana Garg1, Jorge M Blando2, Carlos J Perez3
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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.
Insights
Protein kinase C epsilon (PKCε) and Pten loss cooperate to drive prostate cancer by upregulating chemokine CXCL13. Targeting the CXCL13-CXCR5 axis offers a potential therapeutic strategy for prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Protein kinase C epsilon (PKCε) is an oncogenic protein frequently overexpressed in epithelial cancers.
- The functional interactions of PKCε with genetic alterations and its downstream effectors in tumorigenesis are not well understood.
Purpose of the Study:
- To investigate the cooperative role of PKCε and Pten loss in prostate cancer development.
- To elucidate the molecular mechanisms by which PKCε and Pten loss promote prostate cancer progression.
- To explore the therapeutic potential of targeting the CXCL13-CXCR5 axis.
Main Methods:
- Utilized a mouse model of prostate cancer.
- Performed mechanistic analysis to identify molecular pathways involved.
- Investigated the role of chemokine CXCL13 and its receptor CXCR5 in cancer cell migration and tumorigenicity.
Main Results:
- PKCε cooperates with Pten loss in prostate cancer development.
- PKCε overexpression and Pten loss synergistically upregulate CXCL13 production via the non-canonical NF-κB pathway.
- Disruption of CXCL13 or CXCR5 impaired prostate cancer cell migration and tumorigenicity.
Conclusions:
- PKCε drives an autonomous vicious cycle in prostate cancer.
- The CXCL13-CXCR5 axis is a key mediator of PKCε-driven prostate tumorigenesis and metastasis.
- Targeting the CXCL13-CXCR5 axis represents a promising therapeutic strategy for prostate cancer.