Target gene-specific regulation of androgen receptor activity by p42/p44 mitogen-activated protein kinase.
Open accessAbstract
Evidence that the androgen receptor (AR) is not only important in androgen-dependent prostate cancer, but also continues to play a role in tumors that become resistant to androgen deprivation therapies, highlights the need to find alternate means to block AR activity. AR, a hormone-activated transcription factor, and its coactivators are phosphoproteins. Thus, we sought to determine whether inhibition of specific cell signaling pathways would reduce AR function. We found that short-term inhibition of p42/p44 MAPK activity either by a MAPK kinase inhibitor, U0126, or by depletion of kinase with small interfering RNA caused target gene-specific reductions in AR activity. AR enhances histone H3 acetylation of target genes that are sensitive to U0126 including prostate-specific antigen and TMPRSS2, but does not increase histone H3 acetylation of the U0126-resistant PMEPA1 gene. Thus, although AR induces transcription of many target genes, the molecular changes induced by AR at the chromatin level are target gene specific. Long-term treatment (24-48 h) with U0126 causes a G1 cell cycle arrest and reduces AR expression both through a decrease in AR mRNA and a reduction in AR protein stability. Thus, treatments that reduce p42/p44 MAPK activity in prostate cancer have the potential to reduce AR activity through a reduction in expression levels as well as by target gene-selective inhibition of AR function.
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Treatment of LNCaP and C4-2 cells with the MAPK kinase inhibitor UO126 strongly reduces the amount of AR protein in both the presence and absence of androgen.
“The expression of the AR itself is regulated, in part, by this branch of the MAPK pathway, because treatment of LNCaP and C4-2 cells with the MAPK kinase inhibitor UO126 strongly reduces the amount of AR protein in both the presence and absence of androgen (45).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [45]
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Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer
Lamont, K. R., & Tindall, D. J. (2011) · Molecular Endocrinology · doi:10.1210/me.2010-0469 · Cited by 150 · see citing works
- Authors
- Agoulnik, I. U., Bingman, W. E., Nakka, M., Li, W., Wang, Q., Liu, X. S., Brown, M., & Nancy L., N. L.
- Affiliations
- Department of Molecular and Cellular Biology (I.U.A., W.E.B., M.N., W.L., N.L.W.), Houston Texas 77030
- Dan L Duncan Comprehensive Cancer Center (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2008-11-01
- Volume
- 22
- Issue
- 11
- Pages
- 2420-2432
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC2582542
- OpenAlex
- W2002685287
- Cited by
- 36
- References
- 46
- Citations by year
- 2026: 1 · 2021: 1 · 2018: 1 · 2016: 1 · 2015: 2 · 2014: 3 · 2013: 5 · 2012: 4
- FWCI
- 5.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA58204)
- National Human Genome Research Institute (R01HG004069)
- National Cancer Institute (CA-58204, P50CA058204)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK65262, T32DK007696, T32 DK-07696)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- androgen receptor, p44/42 MAPK, MAPK kinase inhibition, U0126, prostate cancer, androgen deprivation therapy resistance, histone H3 acetylation, prostate-specific antigen, TMPRSS2, PMEPA1, G1 cell cycle arrest, chromatin regulation
- MeSH terms
- Acetylation, Base Sequence, Binding Sites, Butadienes, Enhancer Elements, Genetic, Histones, Humans, Male, Nitriles, Promoter Regions, Genetic, Prostatic Neoplasms, Receptors, Androgen, RNA, Messenger, RNA, Neoplasm, Mitogen-Activated Protein Kinase 1, MAP Kinase Signaling System, RNA, Small Interfering, Cell Line, Tumor, Protein Kinase Inhibitors, Mitogen-Activated Protein Kinase 3, Protein Stability
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