# Protein kinase C signaling in prostate cancer health disparities

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $576,595

## Abstract

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
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 its 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, database analysis
suggests higher PKCa expression in AA relative to EA prostate tumors. 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 (PKCa-null/TRAMP mice) and syngeneic
models (orthotopic implantation of TRAMP-derived PCa cells) towards the goal of establishing the in vivo
functional relevance of PKCa in prostate tumorigenesis and metastasis. We will authenticate the findings in vivo
using a pharmacological (PKCa inhibitor) approach. In Aim 3 we will determine the relevance of prostate cancer
cell PKCa in the control of the tumor immune landscape and gene expression. We will pursue a thorough
characterization of immune cell populations and cytokine expression in mouse prostate tumors upon inducible
silencing of PKCa. 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 that is a hallmark of
PCa in AA men. In addition to revealing a novel biomarker for...

## Key facts

- **NIH application ID:** 11164144
- **Project number:** 7R01CA276082-02
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Marcelo G. Kazanietz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $576,595
- **Award type:** 7
- **Project period:** 2023-06-08 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11164144

## Citation

> US National Institutes of Health, RePORTER application 11164144, Protein kinase C signaling in prostate cancer health disparities (7R01CA276082-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/11164144. Licensed CC0.

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