Linked Life Data

12727841

Source:http://linkedlifedata.com/resource/pubmed/id/12727841

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2003-5-2
pubmed:abstractText
To date, no effective treatment for patients with advanced androgen-independent prostate cancer is available, whereas androgen ablation therapy, surgery, and radiation therapy are effective in treating local, androgen-dependent tumors. The mechanisms underlying the differences between androgen-dependent and -independent prostate cancer remain elusive. Interleukin (IL)-6 is a pleiotropic cytokine whose expression under normal physiological conditions is tightly controlled. However, aberrant constitutive IL-6 gene expression has been implicated in prostate cancer progression and resistance to chemotherapy and has been directly linked to prostate cancer morbidity and mortality. Particularly striking is the large increase in the expression of IL-6 in hormone-refractory prostate cancer. IL-6, in addition to its role as an immunomodulatory cytokine, functions as a growth and differentiation factor for prostate cancer cells. To determine the molecular mechanisms that lead to deregulated IL-6 expression in advanced prostate cancer, we examined the regulatory elements involved in IL-6 gene expression in androgen-independent prostate cancer cells. We demonstrate that, in contrast to the androgen-sensitive LNCaP cells, androgen-insensitive PC-3 and DU145 cells express high levels of IL-6 protein and mRNA due to enhanced promoter activity. Deregulated activation of the IL-6 promoter is for the most part mediated by a combined constitutive activation of the nuclear factor (NF)-kappaB p50 and p65 and the activator protein 1 (AP-1) JunD and Fra-1 family members as demonstrated by electrophoretic mobility shift assays, site-directed mutagenesis, and transfection experiments. Mutation of the NF-kappaB and AP-1 sites drastically reduces IL-6 promoter activity in both androgen-independent prostate cancer cell lines. Additionally, inhibition of these transcription factors using adenovirus vectors encoding either the IkappaBalpha repressor gene or a dominant negative JunD mutant leads to a strong down-regulation of IL-6 gene expression at the mRNA and protein level as measured by real-time PCR and ELISA, respectively. Furthermore, the blockade of IL-6 gene expression results in drastic inhibition of the constitutively activated signal transducers and activators of transcription 3 signaling pathway in DU145 cells. Our data demonstrate for the first time that a combined aberrant activation of NF-kappaB p50 and p65 and AP-1 JunD and Fra-1 in androgen-independent prostate cancer cells results in deregulated IL-6 expression, suggesting a novel potential entry point for therapeutic intervention in prostate cancer.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins, http://linkedlifedata.com/resource/pubmed/chemical/I-kappa B Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-6, http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B, http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B p50 Subunit, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-fos, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-jun, http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger, http://linkedlifedata.com/resource/pubmed/chemical/STAT3 Transcription Factor, http://linkedlifedata.com/resource/pubmed/chemical/STAT3 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators, http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factor RelA, http://linkedlifedata.com/resource/pubmed/chemical/fos-related antigen 1
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
63
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2206-15
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:12727841-DNA-Binding Proteins, pubmed-meshheading:12727841-Down-Regulation, pubmed-meshheading:12727841-Gene Expression Regulation, Neoplastic, pubmed-meshheading:12727841-Humans, pubmed-meshheading:12727841-I-kappa B Proteins, pubmed-meshheading:12727841-Interleukin-6, pubmed-meshheading:12727841-Male, pubmed-meshheading:12727841-NF-kappa B, pubmed-meshheading:12727841-NF-kappa B p50 Subunit, pubmed-meshheading:12727841-Neoplasms, Hormone-Dependent, pubmed-meshheading:12727841-Phosphorylation, pubmed-meshheading:12727841-Promoter Regions, Genetic, pubmed-meshheading:12727841-Prostatic Neoplasms, pubmed-meshheading:12727841-Proto-Oncogene Proteins c-fos, pubmed-meshheading:12727841-Proto-Oncogene Proteins c-jun, pubmed-meshheading:12727841-RNA, Messenger, pubmed-meshheading:12727841-STAT3 Transcription Factor, pubmed-meshheading:12727841-Trans-Activators, pubmed-meshheading:12727841-Transcription Factor RelA, pubmed-meshheading:12727841-Transcriptional Activation, pubmed-meshheading:12727841-Transfection, pubmed-meshheading:12727841-Tumor Cells, Cultured
pubmed:year
2003
pubmed:articleTitle
Constitutive activation of nuclear factor kappaB p50/p65 and Fra-1 and JunD is essential for deregulated interleukin 6 expression in prostate cancer.
pubmed:affiliation
BIDMC Genomics Center and New England Baptist Bone and Joint Institute, Boston, Massachusetts 02115, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S.