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Androgen receptor targets NFKB and TSPI to suppress prostate tumor growth in vivo
Nelius, Thomas; Filleur, Stephanie; Yemelyanov, Alexander; Budunova, Irina; Shroff, E.; Mirochnik, Yelena; Aurora, Arin; Veliceasa, Dorina; Xiao, Wuhan; Wang, Zhou; Volpert, Olga V.; Volpert, OV, Northwestern Univ, Feinberg Sch Med, Dept Urol, 303 E Chicago Ave, Chicago, IL 60611 USA
2007-09-01
Source PublicationINTERNATIONAL JOURNAL OF CANCER
ISSN0020-7136
Volume121Issue:5Pages:999-1008
AbstractThe androgen role in the maintenance of prostate epithelium is subject to conflicting opinions. While androgen ablation drives the regression of normal and cancerous prostate, testosterone may cause both proliferation and apoptosis. Several investigators note decreased proliferation and stronger response to chemotherapy of the prostate cancer cells stably expressing androgen receptor (AR), however no mechanistic explanation was offered. In this paper we demonstrate in vivo anti-tumor effect of the AR on prostate cancer growth and identify its molecular mediators. We analyzed the effect of AR on the tumorigenicity of prostate cancer cells. Unexpectedly, the AR-expressing cells formed tumors in male mice at a much lower rate than the AR-negative controls. Moreover, the AR-expressing tumors showed decreased vascularity and massive apoptosis. AR expression lowered the angiogenic potential of cancer cells, by increasing secretion of an anti-angiogenic protein, thrombospondin-1. AR activation caused a decrease in RelA, a subunit of the pro-survival transcription factor NF kappa B, reduced its nuclear localization and transcriptional activity. This, in turn, diminished the expression of its anti-apoptotic targets, Bcl-2 and IL-6. Increased apoptosis within AR-expressing tumors was likely due to the NF kappa B suppression, since it was restricted to the cells lacking nuclear (active) NF kappa B. Thus we for the first time identified combined decrease of NF kappa B and increased TSP1 as molecular events underlying the AR anti-tumor activity in vivo. Our data indicate that intermittent androgen ablation is preferable to continuous withdrawal, a standard treatment for early-stage prostate cancer. (C) 2007 Wiley-Liss, Inc.; The androgen role in the maintenance of prostate epithelium is subject to conflicting opinions. While androgen ablation drives the regression of normal and cancerous prostate, testosterone may cause both proliferation and apoptosis. Several investigators note decreased proliferation and stronger response to chemotherapy of the prostate cancer cells stably expressing androgen receptor (AR), however no mechanistic explanation was offered. In this paper we demonstrate in vivo anti-tumor effect of the AR on prostate cancer growth and identify its molecular mediators. We analyzed the effect of AR on the tumorigenicity of prostate cancer cells. Unexpectedly, the AR-expressing cells formed tumors in male mice at a much lower rate than the AR-negative controls. Moreover, the AR-expressing tumors showed decreased vascularity and massive apoptosis. AR expression lowered the angiogenic potential of cancer cells, by increasing secretion of an anti-angiogenic protein, thrombospondin-1. AR activation caused a decrease in RelA, a subunit of the pro-survival transcription factor NF kappa B, reduced its nuclear localization and transcriptional activity. This, in turn, diminished the expression of its anti-apoptotic targets, Bcl-2 and IL-6. Increased apoptosis within AR-expressing tumors was likely due to the NF kappa B suppression, since it was restricted to the cells lacking nuclear (active) NF kappa B. Thus we for the first time identified combined decrease of NF kappa B and increased TSP1 as molecular events underlying the AR anti-tumor activity in vivo. Our data indicate that intermittent androgen ablation is preferable to continuous withdrawal, a standard treatment for early-stage prostate cancer. (C) 2007 Wiley-Liss, Inc.
SubtypeArticle
KeywordProstate Cancer Androgen Receptor Nf Kappa b Angiogenesis Apoptosis
DepartmentNorthwestern Univ, Feinberg Sch Med, Dept Urol, Chicago, IL 60611 USA; Northwestern Univ, Feinberg Sch Med, Dept Pulm Med, Chicago, IL 60611 USA; Texas Tech Univ, Hlth Sci Ctr, Dept Urol, Lubbock, TX 79409 USA; Northwestern Univ, Feinberg Sch Med, Dept Dermatol, Chicago, IL 60611 USA; Chinese Acad Sci, Inst Hydrobiol, Wuhan, Peoples R China; Univ Pittsburgh, Dept Urol, Pittsburgh, PA 15260 USA; Univ Pittsburgh, Pittsburgh Canc Inst, Pittsburgh, PA 15260 USA
Subject AreaOncology
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
Indexed BySCI
Language英语
WOS Research AreaOncology
WOS SubjectOncology
WOS IDWOS:000248242500009
WOS KeywordFACTOR-KAPPA-B ; HUMAN ENDOTHELIAL-CELLS ; CANCER CELLS ; INTRAEPITHELIAL NEOPLASIA ; CONSTITUTIVE ACTIVATION ; VENTRAL PROSTATE ; RESPONSE ELEMENT ; TYROSINE KINASE ; ATHYMIC MICE ; MOUSE MODELS
Citation statistics
Cited Times:41[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.ihb.ac.cn/handle/152342/8490
Collection期刊论文
Corresponding AuthorVolpert, OV, Northwestern Univ, Feinberg Sch Med, Dept Urol, 303 E Chicago Ave, Chicago, IL 60611 USA
Affiliation1.Northwestern Univ, Feinberg Sch Med, Dept Urol, Chicago, IL 60611 USA
2.Northwestern Univ, Feinberg Sch Med, Dept Pulm Med, Chicago, IL 60611 USA
3.Texas Tech Univ, Hlth Sci Ctr, Dept Urol, Lubbock, TX 79409 USA
4.Northwestern Univ, Feinberg Sch Med, Dept Dermatol, Chicago, IL 60611 USA
5.Chinese Acad Sci, Inst Hydrobiol, Wuhan, Peoples R China
6.Univ Pittsburgh, Dept Urol, Pittsburgh, PA 15260 USA
7.Univ Pittsburgh, Pittsburgh Canc Inst, Pittsburgh, PA 15260 USA
Recommended Citation
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Nelius, Thomas,Filleur, Stephanie,Yemelyanov, Alexander,et al. Androgen receptor targets NFKB and TSPI to suppress prostate tumor growth in vivo[J]. INTERNATIONAL JOURNAL OF CANCER,2007,121(5):999-1008.
APA Nelius, Thomas.,Filleur, Stephanie.,Yemelyanov, Alexander.,Budunova, Irina.,Shroff, E..,...&Volpert, OV, Northwestern Univ, Feinberg Sch Med, Dept Urol, 303 E Chicago Ave, Chicago, IL 60611 USA.(2007).Androgen receptor targets NFKB and TSPI to suppress prostate tumor growth in vivo.INTERNATIONAL JOURNAL OF CANCER,121(5),999-1008.
MLA Nelius, Thomas,et al."Androgen receptor targets NFKB and TSPI to suppress prostate tumor growth in vivo".INTERNATIONAL JOURNAL OF CANCER 121.5(2007):999-1008.
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