title: IκB-Kinase-epsilon (IKKε) over-expression promotes the growth of prostate cancer through the C/EBP-β 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 (IKKε also named IKKi or IκBKε) 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 IKKε expression and IL-6 secretion. In the present study, we validated the impact of IKKε depletion on the in vitro proliferation of castrate-resistant prostate cancer cells, and characterized how IKKε depletion affects tumor growth and IL-6 tumor secretion in vivo through a mouse xenograft-based approach. We observed a significant growth delay in IKKε-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 IKKε over-expression induces a NF-κB-independent stimulation of the IL-6 gene promoter through the activation and nuclear accumulation of the transcription factor C/EBP-β. Our study demonstrates the pro-proliferative role of the oncogene IKKε in castrate-resistant prostate cancer cell lines, involving the phosphorylation and nuclear translocation of C/EBP-β that initiates IL-6 gene expression.
authors: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)/Institut du Cancer de Montréal, Montreal, Canada.
authors: Benjamin
authors: B
authors: Péant
authors: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)/Institut du Cancer de Montréal, Montreal, Canada.
authors: Sophie
authors: S
authors: Gilbert
authors: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)/Institut du Cancer de Montréal, Montreal, Canada.
authors: Cécile
authors: C
authors: Le Page
authors: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)/Institut du Cancer de Montréal, Montreal, Canada.
authors: Alexis
authors: A
authors: Poisson
authors: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)/Institut du Cancer de Montréal, Montreal, Canada.
authors: Emilie
authors: E
authors: L'Ecuyer
authors: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)/Institut du Cancer de Montréal, Montreal, Canada.
authors: Zied
authors: Z
authors: Boudhraa
authors: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)/Institut du Cancer de Montréal, Montreal, Canada.
authors: Marc Nicolas
authors: MN
authors: Bienz
authors: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)/Institut du Cancer de Montréal, Montreal, Canada.
authors: Nathalie
authors: N
authors: Delvoye
authors: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)/Institut du Cancer de Montréal, Montreal, Canada.|Department of Surgery, Hôpital Saint Luc (CHUM), Montreal, Canada.|Department of Surgery, Université de Montréal, Montreal, Canada.
authors: Fred
authors: F
authors: Saad
authors: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)/Institut du Cancer de Montréal, Montreal, Canada.|Department of Medicine, Université de Montréal, Montreal, Canada.
authors: Anne-Marie
authors: AM
authors: Mes-Masson
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D051550:I-kappa B Kinase
keywords: C/EBP-β; IKKε; IL-6 gene promoter; cell proliferation; prostate cancer