# Dissecting the Role of Proteostasis in Anti-Androgen Resistant Prostate Cancer

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $341,181

## Abstract

PROJECT ABSTRACT
In the United States, prostate cancer (PCa) is predicted to be the second leading cause of cancer related
death in men in the United States in 2020. After initial diagnosis of PCa, radical prostatectomy, radiation and
androgen deprivation therapy (ADT) are used to treat the primary tumors. When cancer recurs, castrate-
resistant prostate cancer (CRPC) is treated by anti-androgen drugs, such as enzalutamide (XTANDI®),
abiraterone acetate (ZYTIGA®) or apalutamide (ERLEADA™). Although these drugs are highly effective initially,
patients quickly develop resistance through mechanisms that are not completely understood. Therefore, there
is an urgent need to identify resistant mechanisms to improve the treatment outcome of CRPC. Protein
homeostasis (proteostasis) deficiency and oncogenic activation plays important roles during tumorigenesis;
however, proteostasis modulation involved in anti-androgen resistant PCa is still rudimentarily understood. We
have reported that ubiquitin mediated proteolysis pathway and proteasome activity are suppressed in
enzalutamide and abiraterone resistant PCa cells. As a result, androgen receptor (AR) and its variant form AR-
V7 protein are stabilized and accumulated in these resistant cells through chaperone-ubiquitin-proteasome-
system alteration. The chaperone (Hsp70)/E3 ubiquitin ligase (Stub1) machinery regulates full length AR and
AR variant proteostasis. Hsp70 inhibition by small molecules promotes Hsp70, AR-V7 and Stub1 proximity
which significantly disrupts AR/AR-V7 gene programs and suppresses prostate tumor growth. This proposal
initiates a new paradigm to explore the underlying mechanisms driving next generation anti-androgen
resistance in CRPC. The ultimate goal of this program is to dissect the roles of chaperone-ubiquitin-
proteasome-system in anti-androgen resistance and develop new pharmaceutical approaches to provide co-
targeting neoadjuvant with anti-AR agents to personalized CRPC patients’ treatment. We will provide a novel
mechanism of next generation anti-androgen resistance via proteostasis impairment and uncover that
Hsp70/Stub1 machinery in anti-androgen resistant CRPC may trigger accumulation of oncogenic proteins such
as AR variants and glucocorticoid receptor (GR) due to inability of protein clearance. We will functionally
interrogate the Hsp70/Stub1/AR-V7 ternary complex through biochemical assays, and uncover the
mechanisms of inhibition of Hsp70 activity in inducing AR-V7 degradation through the proximity of Stub1. We
will unveil the underlying mechanisms of AR and AR-V7 ubiquitination through the ubiquitination binding sites
identification and large-scale ubiquitin remnants sequencing. Importantly, we will provide the rationale to
correct proteostasis imbalance through modulation of Hsp70/Stub1 as a potential therapeutic strategy to
overcome resistance to AR-targeted therapies in CRPC patients and develop conditional reprogramed cell
cultures (CRCs) and patient derived xen...

## Key facts

- **NIH application ID:** 10930002
- **Project number:** 5R37CA249108-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Chengfei Liu
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $341,181
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10930002

## Citation

> US National Institutes of Health, RePORTER application 10930002, Dissecting the Role of Proteostasis in Anti-Androgen Resistant Prostate Cancer (5R37CA249108-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10930002. Licensed CC0.

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