Dataset Information

I?B-Kinase-epsilon (IKK?) over-expression promotes the growth of prostate cancer through the C/EBP-? dependent activation of IL-6 gene expression.

ABSTRACT: The inflammatory cytokine IL-6 has been shown to induce the nuclear translocation of androgen receptors in prostate cancer cells and to activate the androgen receptors in a ligand-independent manner, suggesting it may contribute to the development of a castrate-resistant phenotype. Elevated IL-6 serum levels have also been associated with metastasis-related morbidity in prostate cancer patients. We have previously established that over-expression of I-kappa-B-kinase-epsilon (IKK? also named IKKi or I?BK?) in hormone-sensitive prostate cancer cell lines induces IL-6 secretion. We have also reported that prostate cancer cell lines lacking androgen receptor expression exhibit high constitutive IKK? expression and IL-6 secretion. In the present study, we validated the impact of IKK? depletion on the in vitro proliferation of castrate-resistant prostate cancer cells, and characterized how IKK? depletion affects tumor growth and IL-6 tumor secretion in vivo through a mouse xenograft-based approach. We observed a significant growth delay in IKK?-silenced PC-3 cells injected in SCID mice fed with a doxycycline-supplemented diet in comparison with mice fed with a normal diet. We also found a decrease in IL-6 secretion levels that strongly correlated with tumor growth inhibition. Finally, using constructs with various IL-6-mutated promoters, we demonstrated that IKK? over-expression induces a NF-?B-independent stimulation of the IL-6 gene promoter through the activation and nuclear accumulation of the transcription factor C/EBP-?. Our study demonstrates the pro-proliferative role of the oncogene IKK? in castrate-resistant prostate cancer cell lines, involving the phosphorylation and nuclear translocation of C/EBP-? that initiates IL-6 gene expression.

SUBMITTER: Peant B

PROVIDER: S-EPMC5362420 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

IκB-Kinase-epsilon (IKKε) over-expression promotes the growth of prostate cancer through the C/EBP-β dependent activation of IL-6 gene expression.

Péant Benjamin B Gilbert Sophie S Le Page Cécile C Poisson Alexis A L'Ecuyer Emilie E Boudhraa Zied Z Bienz Marc Nicolas MN Delvoye Nathalie N Saad Fred F Mes-Masson Anne-Marie AM

Oncotarget 20170201 9

The inflammatory cytokine IL-6 has been shown to induce the nuclear translocation of androgen receptors in prostate cancer cells and to activate the androgen receptors in a ligand-independent manner, suggesting it may contribute to the development of a castrate-resistant phenotype. Elevated IL-6 serum levels have also been associated with metastasis-related morbidity in prostate cancer patients. We have previously established that over-expression of I-kappa-B-kinase-epsilon (IKKε also named IKKi ...[more]

PMID: 27577074

Similar Datasets

Project description:Transcription factor C/EBP-beta regulates a number of physiological responses. During an investigation of the growth-suppressive effects of interferons (IFNs), we noticed that cebpb(-/-) cells fail to undergo apoptosis upon gamma IFN (IFN-gamma) treatment, compared to wild-type controls. To examine the basis for this response, we have performed gene expression profiling of isogenic wild-type and cebpb(-/-) bone marrow macrophages and identified a number of IFN-gamma-regulated genes that are dependent on C/EBP-beta for their expression. These genes are distinct from those regulated by the JAK-STAT pathways. Genes identified in this screen appear to participate in various cellular pathways. Thus, we identify a new pathway through which the IFNs exert their effects on cellular genes through C/EBP-beta. One of these genes is death-associated protein kinase 1 (dapk1). DAPK1 is critical for regulating the cell cycle, apoptosis, and metastasis. Using site-directed mutagenesis, RNA interference, and chromatin immunoprecipitation assays, we show that C/EBP-beta binds to the promoter of dapk1 and is required for the regulation of dapk1. Both mouse dapk1 and human dapk1 exhibited similar dependences on C/EBP-beta for their expression. The expression of the other members of the DAPK family occurred independently of C/EBP-beta. Members of the C/EBP family of transcription factors other than C/EBP-beta did not significantly affect dapk1 expression. We identified two elements in this promoter that respond to C/EBP-beta. One of these is a consensus C/EBP-beta-binding site that constitutively binds to C/EBP-beta. The other element exhibits homology to the cyclic AMP response element/activating transcription factor binding sites. C/EBP-beta binds to this site in an IFN-gamma-dependent manner. Inhibition of ERK1/2 or mutation of an ERK1/2 site in the C/EBP-beta protein suppressed the IFN-gamma-induced response of this promoter. Together, our data show a critical role for C/EBP-beta in a novel IFN-induced cell growth-suppressive pathway via DAPK1.

Dataset Information

I?B-Kinase-epsilon (IKK?) over-expression promotes the growth of prostate cancer through the C/EBP-? dependent activation of IL-6 gene expression.

Publications

IκB-Kinase-epsilon (IKKε) over-expression promotes the growth of prostate cancer through the C/EBP-β dependent activation of IL-6 gene expression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets