# MAOA and AR Reciprocal Crosstalk in Prostate Cancer

> **NIH NIH R37** · WASHINGTON STATE UNIVERSITY · 2024 · $332,489

## Abstract

Project Summary/Abstract (Parent Grant Application)
Prostate cancer (PC) is the most common non-skin cancer in American men, with a lifetime incidence of 1 in 7,
and also the second leading cause of cancer death in American men. Androgen receptor (AR) is the primary
oncogenic driver of PC growth, survival and progression. AR-directed therapy is currently the principal
treatment regimen. Despite initial response rates exceeding 90%, PC eventually relapses and progresses to
fatal castration-resistant PC (CRPC), where reactivation of AR signaling occurs in a low-androgen environment.
Recent introduction of FDA-approved next-generation antiandrogens, including enzalutamide (ENZ) and
abiraterone acetate (ABI), have improved the CRPC treatment landscape, but emergence of drug resistance
remains nearly universal, with no AR-targeted therapeutic options afterwards. These dismal facts underscore
the pressing clinical need to identify new molecular targets and develop effective therapies to combat
advanced PC. Through integrated analysis of publicly available clinical PC data sets coupled with functional
studies in AR-positive PC cells, we propose monoamine oxidase A (MAOA), which synergizes with AR to
promote PC, as an ideal therapeutic candidate to complement AR-targeted therapy in CRPC. We identified a
novel reciprocal interaction between MAOA and AR in PC cells. MAOA expression is induced by androgen
treatment; and conversely, MAOA silencing significantly reduces AR activity by lowering AR target gene
expression and responsiveness to androgen stimulation in PC cells under both androgen-replete and depleted
conditions as well as in a CRPC xenograft model. We showed significant positive co-expression of MAOA and
AR target genes (PSA, TMPRSS2, NKX3.1) in multiple clinical data sets, including CRPC. Importantly, we
found MAOA genomic amplification and/or epigenetic activation in 64% of samples in a CRPC data set,
reinforced by elevated MAOA protein expression in our CRPC patient cohort. Additionally, we demonstrated
that inhibition of MAOA by genetic or pharmacological approaches enhanced the growth-inhibiting effects of
ENZ and ABI in androgen-sensitive, CR and antiandrogen-resistant PC cells. Based on these findings, we will
test the hypothesis that MAOA synergizes with AR through reciprocal crosstalk and convergent downstream
signaling to amply MAOA/AR effects promoting AR-driven PC growth and progression, and that co-targeting
MAOA/AR is an actionable, effective strategy to treat CRPC and reverse antiandrogen drug resistance. To
address this hypothesis, three aims are proposed. In Aim 1, we will elucidate the mechanistic basis of MAOA-
AR reciprocal interaction in PC cells. In Aim 2, we will characterize the role of MAOA in regulating the
development and progression of CRPC in xenograft models. In Aim 3, we will determine the efficacy of MAOA
inhibitors for treating CRPC and reversing resistance to next-generation antiandrogens in vitro and in vivo.
Th...

## Key facts

- **NIH application ID:** 10657282
- **Project number:** 4R37CA233658-06
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Boyang Wu
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $332,489
- **Award type:** 4N
- **Project period:** 2019-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10657282

## Citation

> US National Institutes of Health, RePORTER application 10657282, MAOA and AR Reciprocal Crosstalk in Prostate Cancer (4R37CA233658-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10657282. Licensed CC0.

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