# Role of proinflammatory cytokine-induced AR degradation in castration-resistant prostate cancer

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $377,625

## Abstract

PROJECT SUMMARY
The androgen receptor (AR) remains the major therapeutic target of castration-resistant prostate cancer
(CRPC). However, most patients develop resistance and at present there is no drug that enables to
completely inhibit AR activity or eliminate AR protein. Increasing evidence suggests that proinflammatory
cytokines such as tumor necrosis factor-α (TNFα) induce activation of IκB kinase-β (IKKβ), which in turn
promotes the activation of the oncogenic transcription factor NFκB and survival of cancerous cells. However,
the outcomes of rationalized chemoprevention trials using anti-inflammation drugs have been mixed, stressing
an urgent need to unfold the precise role of inflammation in prostate cancer (PCa). Our preliminary data
showed that TNFα induces ubiquitination and proteasomal degradation of AR protein in androgen-sensitive,
but not certain castration-resistant PCa cell lines. We further showed that IKKβ is required for TNFα-induced
degradation of AR in PCa cells. Consistent with our finding that the AR protein harbors two putative IKKβ
phosphorylation sites, which overlap with the phosphodegron motif recognized by the β-TRCP E3 ubiquitin
ligase, we found that β-TRCP1 and β-TRCP2 interact with and promote degradation of AR protein. Moreover,
we demonstrated that expression of tumor necrosis factor receptor-associated death domain (TRADD) protein,
an upstream activator of IKKβ, is required for TNFα-induced AR degradation, but its expression is
downregulated or lost in CRPC xenografts and patient samples. Furthermore, we demonstrated that inhibition
of AR activity by abiraterone acetate (ABI), a next-generation anti-AR agent, decreased prostate tumor burden
in castrated Pten knockout (KO) mice. RNA-seq analysis of ABI-based clinical trial samples showed that
expression of TRADD mRNA was much lower in some CRPC patients than others. Based upon these novel
preliminary data, we hypothesize that while proinflammatory cytokines such as TNFα promotes IKKβ-mediated
activation of NFκB signaling, activated IKKβ also induces β-TRCP-dependent ubiquitination and degradation of
AR, a major promoter of PCa, thereby antagonizing PCa progression. We further hypothesize that inactivation
of the components of the IKKβ signaling pathway, such as loss or reduced expression of TRADD, blocks IKKβ-
mediated degradation of AR, thereby promoting AR protein elevation, anti-AR therapy resistance and PCa
progression. To test this novel hypothesis, we will determine the molecular mechanism and functional
importance of IKKβ-mediated AR degradation in response to the inflammatory cytokine in PCa cells (Aim 1),
and determine the biological importance and clinical significance of deregulation of the TRADD-IKKβ-AR axis
in castration-resistant progression of PCa using mouse models and patient specimens (Aim 2). The findings
from the study will not only shed new light on the mechanisms of AR protein degradation and identification of
novel signaling pathways to eli...

## Key facts

- **NIH application ID:** 9951004
- **Project number:** 5R01CA130908-11
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Haojie Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $377,625
- **Award type:** 5
- **Project period:** 2010-06-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9951004

## Citation

> US National Institutes of Health, RePORTER application 9951004, Role of proinflammatory cytokine-induced AR degradation in castration-resistant prostate cancer (5R01CA130908-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9951004. Licensed CC0.

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