# Novel mechanisms of SKP2 and AR signaling on the suppression of prostate cancer

> **NIH NIH U54** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $11,881

## Abstract

SUMMARY
Prostate Cancer (PCa) is the second-leading cause of cancer-related deaths in American men. The morbidity
and the mortality to PCa are 2.44-fold higher in African American men as compared to Caucasian counterparts.
Therapies such as surgery, radiation and androgen-ablation have been developed to control PCa for patients at
different stages. However, the relapse of this disease is reported in many cases, particularly in patients at
advanced stage-metastasis, and as a result patients eventually died of the recurrent growth of castration
resistant prostate cancer (CRPC). Studies demonstrated that various alterations of tumor suppressors and
oncogenes contribute to the initiation and progression of PCa as well as the recurrent growth of CRPC. Emerging
evidence revealed that CRPC growth is a complicated malignancy with dysregulation of multiple oncogenic
pathways. Mechanisms on the oncogenic signaling pathways leading to CRPC are poorly understood, and their
aberrant activations are regulated in a context and environment dependent manner. Yet, it is urgent to explore
novel drugs and further to develop efficient treatments in order to reduce the incidence and mortality rate of PCa
and to eliminate the disparities among ethnic groups. Aberrant elevation of SKP2 and AR are frequently found
in advanced PCa and CRPC. We discovered that SKP2 inactivation partially suppresses PCa progression but
also leads to aberrant elevation of AR and FOXA1 pathways. We HYPOTHESIZE that AR elevation confers
resistance to SKP2 inhibition in prostate cancer cells and a combined inhibition of SKP2 and AR can effectively
suppress the CRPC growth. We propose to test this hypothesis by evaluating the molecular profiling of
FOXA1/AR regulated by SKP2, the anti-proliferation effects of co-targeting SKP2 and AR in PCa cells in vitro
and its efficacy of combined treatment on the suppression of prostate tumors in mice in vivo. The following
specific aims are proposed: 1) Define the mechanisms on the regulation of FOXA1/AR pathways by SKP2 in
PCa cells; 2) Study the molecular profiling of FOXA1/AR signaling by SKP2 in PCa cells; and 3) Investigate the
efficacy of combined targeting of SKP2 and AR inhibition on the suppression of PCa progression in vivo. Results
will provide a novel and efficient therapeutic regimen to suppress CRPC growth.

## Key facts

- **NIH application ID:** 10003182
- **Project number:** 5U54CA163072-11
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** ROBERT J. MATUSIK
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $11,881
- **Award type:** 5
- **Project period:** 2011-09-23 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003182

## Citation

> US National Institutes of Health, RePORTER application 10003182, Novel mechanisms of SKP2 and AR signaling on the suppression of prostate cancer (5U54CA163072-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10003182. Licensed CC0.

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