# Androgen Deprivation Activates Wnt/Beta-Catenin Signaling in Prostate Cancer

> **NIH NIH R01** · LOUISIANA STATE UNIV HSC SHREVEPORT · 2020 · $331,688

## Abstract

SUMMARY
 Androgen deprivation therapy has been the gold standard for the treatment of advanced prostate
cancer (PCa) since the 1960s. Patients initially respond well to the treatment resulting in tumor regression, but
ultimately progress to castrate-resistant PCa for which there is no cure. New anti-androgens have shown
significant improvement in treating PCa patients who failed androgen deprivation therapy. However, even PCa
patients on enzalutamide (the most potent anti-androgen therapy), eventually progress to castrate-resistant
PCa. Moreover, once PCa becomes castrate-resistant, an aggressive neuroendocrine (NE) phenotype ensue
with high morbidity, with only an average survival of less than 1.5 years. There are currently no effective
treatments against PCa with a prominent NE phenotype. Therefore, identifying the mechanism(s) through
which NE phenotype arises as consequence to anti-androgen therapies is critical for the development of novel
therapeutics against PCa. The Wnt/beta-Catenin signaling pathway is prevalent in advanced PCa. We
previously showed that activation of Wnt/beta-Catenin signaling promotes the development of castrate-
resistant PCa with an increased NE phenotype, thus linking the active Wnt/beta-Catenin signaling with
castrate-resistant progression and the emergence of NE phenotype in PCa. Consistent with this, we
corroborated that the Wnt/beta-Catenin pathway is active in the NEPCa. Androgen deprivation has been
shown to accelerate the emergence of the NE phenotype in PCa. Our preliminary data demonstrated that
androgen deprivation upregulated Wnt7a, a Wnt ligand that can activate Wnt/beta-Catenin signaling. Our data
also indicated that androgen deprivation upregulated Dkk1, an endogenous secretory inhibitor of the Wnt/beta-
Catenin signaling, in normal prostates but not in PCa. Based on these observations, we hypothesize that
androgen deprivation activates Wnt/beta-Catenin signaling to promote castrate-resistant progression and NE
differentiation of PCa. This hypothesis will be tested by the following Specific Aims: Aim 1: To determine how
androgen deprivation activates Wnt/beta-Catenin signaling in PCa. Aim 2: To determine the mechanism(s)
through which androgen deprivation modulates Wnt/beta-Catenin signaling by regulating stromal/epithelial
interaction. Aim 3: To determine whether blocking the Wnt/beta-Catenin pathway (via inducible expression of
DKK1 and pharmacological inhibitors) suppresses NEPCa.

## Key facts

- **NIH application ID:** 9966915
- **Project number:** 5R01CA226285-03
- **Recipient organization:** LOUISIANA STATE UNIV HSC SHREVEPORT
- **Principal Investigator:** Xiuping Yu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $331,688
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966915

## Citation

> US National Institutes of Health, RePORTER application 9966915, Androgen Deprivation Activates Wnt/Beta-Catenin Signaling in Prostate Cancer (5R01CA226285-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9966915. Licensed CC0.

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