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Aberrant activation of the androgen receptor by NF-κB2/p52 in prostate cancer cells.
Open accessPublished version of a preprint
Abstract
Prostate cancer initiation and progression are uniquely dependent on the androgen receptor (AR). Even when the cancer progresses to a castration-resistant stage, AR signaling remains active via a variety of mechanisms. In the present study, we showed that NF-kappaB/p52 can activate the AR, resulting in increased transactivation of AR-responsive genes, such as PSA and NKX3.1, in a ligand-independent manner. NF-kappaB2/p52 enhances nuclear translocation and activation of AR by interacting with its NH(2)-terminal domain and enhances the recruitment of coactivators such as p300 to the promoters of AR-dependent genes. These results were confirmed in three different prostate cancer cell lines: LAPC-4 (wild-type AR), LNCaP (mutant AR), and C4-2 (castration resistant). Transfection of p52 into LAPC-4 and LNCaP cells (which express low levels of p52) showed increased activation of the endogenous AR. Downregulation of endogenous p52 in C4-2 cells resulted in abrogation of AR constitutive activation. Comparison of the relative effects of p52 and p65 (RelA) showed that p52, but not p65, could activate the AR. Collectively, these findings, together with previous reports that the levels of NF-kappaB2/p52 are elevated in prostate cancer cells and that active NF-kappaB2/p52 promotes prostate cancer cell growth in vitro and in vivo, suggest that NF-kappaB2/p52 may play a critical role in the progression of castration-resistant prostate cancer.
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“This action of NF-B drives constitutive activity of the AR, because siRNA knockdown of endogenous p52 in C4-2 cells abolished transcription of AR target genes (54).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [54]
In the citing paper
“NF-B/p52 can activate the AR in the absence of androgen in LAPC-4, LNCaP, and C4-2 cells.”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [54]
In the citing paper
“The exact mechanism for this is not clearly understood; however, it appears that at least part of the transactivation is due to NF-B direct interaction with the NH 2 domain of the AR, which allows for recruitment of coactivators like p300 and augmented binding to the promoter regions of AR-targeted genes (54).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [54]
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Metadata
- Authors
- Nadiminty, N., Lou, W., Sun, M., Chen, J., Yue, J., Kung, H.-J., Evans, C. P., Zhou, Q., & Gao, A. C.
- Affiliations
- Tianjin Medical University General Hospital (CN)
- Corresponding author
- Gao, Allen C.
- Venue
- Cancer Research
- Published
- 2010-04-14
- Volume
- 70
- Issue
- 8
- Pages
- 3309-3319
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3041633
- OpenAlex
- W2126127142
- Cited by
- 113
- References
- 49
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 8 · 2021: 3 · 2020: 5 · 2019: 5 · 2018: 10 · 2017: 4 · 2016: 5 · 2015: 9 · 2014: 10 · 2013: 9 · 2012: 7
- FWCI
- 12.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Rochester
- National Cancer Institute (CA118887, R01CA118887, CA 109441, R01CA140468, R01CA109441, PC080538)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Keywords
- androgen receptor, prostate cancer, castration-resistant prostate cancer, ligand-independent receptor activation, p300 coactivator, RelA/p65, prostate-specific antigen, NKX3.1, transcriptional activation, nuclear translocation
- MeSH terms
- Src Homology 2 Domain-Containing, Transforming Protein 1, Cell Nucleus, Humans, Male, Models, Biological, Promoter Regions, Genetic, Prostatic Neoplasms, Receptors, Androgen, Transcriptional Activation, Gene Expression Regulation, Neoplastic, NF-kappa B, Protein Structure, Tertiary, Disease Progression, Cell Line, Tumor, p300-CBP Transcription Factors, Shc Signaling Adaptor Proteins
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