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-? (TNF?) induce activation of I?B kinase-? (IKK?), which in turn promotes the activation of the oncogenic transcription factor NF?B 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 TNF? induces ubiquitination and proteasomal degradation of AR protein in androgen-sensitive, but not certain castration-resistant PCa cell lines. We further showed that IKK? is required for TNF?-induced degradation of AR in PCa cells. Consistent with our finding that the AR protein harbors two putative IKK? phosphorylation sites, which overlap with the phosphodegron motif recognized by the ?-TRCP E3 ubiquitin ligase, we found that ?-TRCP1 and ?-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 IKK?, is required for TNF?-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 TNF? promotes IKK?-mediated activation of NF?B signaling, activated IKK? also induces ?-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 IKK? signaling pathway, such as loss or reduced expression of TRADD, blocks IKK?- 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 IKK?-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-IKK?-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 eliminate AR protein, but also lead to identify new factors that promote castration- resistant phenotype of PCa. This knowledge will lay the foundation for development of new therapeutic strategies for effective treatment of CRPC.

Public Health Relevance

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. This application is designed to determine how the AR protein is degraded by the proteasomal pathway in response to the stimulation of the proinflammatory cytokine TNF? and how deregulation of this signaling pathway leads to AR protein elevation, anti-AR therapy resistance and castration-resistant progression in prostate cancer. This knowledge will not only significantly advance our understanding of the mechanisms underlying AR protein degradation and therapy-resistance in CRPC cells, but also may lead to development of new strategies for effective treatment of CRPC in clinic.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Tumor Cell Biology Study Section (TCB)
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Sathyamoorthy, Neeraja
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Mayo Clinic, Rochester
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