The nuclear factor-κB pathway controls the progression of prostate cancer to androgen-independent growth.
Open accessPublished version of a preprint
Abstract
Typically, the initial response of a prostate cancer patient to androgen ablation therapy is regression of the disease. However, the tumor will progress to an "androgen-independent" stage that results in renewed growth and spread of the cancer. Both nuclear factor-kappaB (NF-kappaB) expression and neuroendocrine differentiation predict poor prognosis, but their precise contribution to prostate cancer progression is unknown. This report shows that secretory proteins from neuroendocrine cells will activate the NF-kappaB pathway in LNCaP cells, resulting in increased levels of active androgen receptor (AR). By blocking NF-kappaB signaling in vitro, AR activation is inhibited. In addition, the continuous activation of NF-kappaB signaling in vivo by the absence of the IkappaBalpha inhibitor prevents regression of the prostate after castration by sustaining high levels of nuclear AR and maintaining differentiated function and continued proliferation of the epithelium. Furthermore, the NF-kappaB pathway was activated in the ARR(2)PB-myc-PAI (Hi-myc) mouse prostate by cross-breeding into a IkappaBalpha(+/-) haploid insufficient line. After castration, the mouse prostate cancer continued to proliferate. These results indicate that activation of NF-kappaB is sufficient to maintain androgen-independent growth of prostate and prostate cancer by regulating AR action. Thus, the NF-kappaB pathway may be a potential target for therapy against androgen-independent prostate cancer.
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Blocking NF-κB by small interfering RNA-mediated knockdown of the IκBα inhibitor inhibits AR activation in prostate cancer cells in vitro.
“Blocking of NF-B by small interfering RNA (siRNA)mediated knockdown of the IB␣ (nuclear factor of light polypeptide gene enhancer in B-cells inhibitor, ␣) inhibitor inhibits AR activation in prostate cancer cells in vitro (53).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [53]
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- Authors
- Jin, R. J., Lho, Y., Connelly, L., Wang, Y., Yu, X., Saint Jean, L., Case, T. C., Ellwood-Yen, K., Sawyers, C. L., Bhowmick, N. A., Blackwell, T. S., Yull, F. E., & Matusik, R. J.
- Affiliations
- 1Vanderbilt Prostate Cancer Center and Department of Urologic Surgery,
- Konkuk University Medical Center (KR)
- 2Department of Cancer Biology, and
- 5Departments of Medicine, Urology, and Molecular and Medical Pharmacology, University of California, Los Angeles, California; and
- Memorial Sloan Kettering Cancer Center (US)
- Vanderbilt University Medical Center (US)
- ORCID
- Venue
- Cancer Research
- Published
- 2008-08-12
- Volume
- 68
- Issue
- 16
- Pages
- 6762-6769
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2840631
- OpenAlex
- W2034575708
- Cited by
- 182
- References
- 51
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 4 · 2023: 7 · 2022: 5 · 2021: 11 · 2020: 7 · 2019: 14 · 2018: 11 · 2017: 8 · 2016: 5 · 2015: 8 · 2014: 19 · 2013: 13 · 2012: 17
- FWCI
- 13.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Prostate Cancer Foundation
- National Institutes of Health (1r01ag023490-01)
- National Institute on Aging (R01-AG023490)
- National Heart, Lung, and Blood Institute (R01HL061419)
- National Cancer Institute (R01 CA76142, R01CA076142)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › 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 › Genetics › Estrogen and related hormone effects
- Keywords
- NF-κB signaling, prostate cancer progression, androgen-independent growth, androgen receptor activation, neuroendocrine differentiation, IκBα, androgen deprivation therapy, LNCaP cells, castration, NF-κB inhibitors, therapeutic target
- MeSH terms
- Androgens, Animals, Castration, Cell Nucleus, Humans, Male, Neoplasms, Hormone-Dependent, Prostatic Neoplasms, Receptors, Androgen, RNA, Messenger, Transcription, Genetic, Tumor Cells, Cultured, Blotting, Western, Signal Transduction, Gene Expression Regulation, Neoplastic, NF-kappa B, Apoptosis, Carcinoma, Neuroendocrine, Mice, Knockout, Disease Progression, Reverse Transcriptase Polymerase Chain Reaction, Mice, I-kappa B Kinase
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