Protein kinase C signaling in prostate cancer health disparities

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ABSTRACT Prostate cancer (PCa), the second leading cause of cancer-related deaths among men in the US, disproportionally affects men of African American (AA) descent, who exhibit greater incidence, faster disease progression and higher rate of mortality than men of European descent (EA). AA men are more likely to present high-grade disease and distant metastasis at the time of diagnosis. The drivers of this disparity are multifactorial, and include socioeconomic, lifestyle and biological factors. Current evidence suggests genetic alterations - such as changes in oncogenic and tumor suppressive genes associated with PCa progression - and the presence of a more inflammatory tumor microenvironment (TME) in prostate tumors from men of African descent as major underlying causes of this racial disparity. However, there is still a limited understanding of the molecular/signaling foundations behind the racial differences in PCa. Here, we identified the diacylglycerol-regulated kinase PKCa as a potential contributor towards racial disparities in PCa. We found PKCa to be aberrantly overexpressed in aggressive PCa cell lines as well as in human PCa. Interestingly, silencing PKCa expression from PCa cells impairs their invasive capacity as well as their ability to form tumors in mice. An in-depth RNA-Seq transcriptome analysis integrated with existing database inquires established PKCa as a crucial determinant for the expression of cytokines known to be dysregulated in prostate tumors from AA men. Most remarkably, expression analysis in patient-derived xenografts (PDXs) revealed higher PKCa levels in AA relative to EA prostate tumors, which associates with the expression of epithelial-to-mesenchymal transition (EMT) markers. This led us to hypothesize that excessive activation of PKCa signaling may contribute to racial disparities in PCa. In Aim 1 we will take advantage of a large collection of primary and metastatic human PCa tumors both from AA and EA men to test the hypothesis that there is disproportionate PKCa expression and/or activation in AA PCa. We will establish potential correlations with Gleason score, disease recurrence and metastatic disease in the available cohorts of AA and EA prostate tumors. In Aim 2 we will use both genetically engineered and syngeneic models towards the goal of establishing the in vivo functional relevance of PKCa in prostate tumorigenesis and metastasis. Racial- related cell/tumor growth differences will be established using EA vs. AA PDXs and organoids derived from these racially diverse set of PDXs. In Aim 3 we will pursue a thorough profiling of immune cell populations and cytokine expression in mouse prostate tumors upon inducible silencing of PKCa. Transcriptome signatures will be established both in mouse models as well as in EA vs. AA PDXs to identify racial differences in PKCa-driven gene expression. This will provide a comprehensive perspective on how tumor cell PKCa contributes to the generation of a pro-inflammatory tumorigenic state and an immunosuppressive landscape, and unearth associated differences based on racial distinction. Our studies should provide exceptionally valuable information on the oncogenic and metastatic pathways leading to racial disparities in PCa.