Research Papers:
IκB-Kinase-epsilon (IKKε) over-expression promotes the growth of prostate cancer through the C/EBP-β dependent activation of IL-6 gene expression
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Abstract
Benjamin Péant1, Sophie Gilbert1,*, Cécile Le Page1,*, Alexis Poisson1,*, Emilie L’Ecuyer1, Zied Boudhraa1, Marc Nicolas Bienz1, Nathalie Delvoye1, Fred Saad1,2,3, Anne-Marie Mes-Masson1,4
1Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)/Institut du Cancer de Montréal, Montreal, Canada
2Department of Surgery, Hôpital Saint Luc (CHUM), Montreal, Canada
3Department of Surgery, Université de Montréal, Montreal, Canada
4Department of Medicine, Université de Montréal, Montreal, Canada
*These authors contributed equally to this work
Correspondence to:
Anne-Marie Mes-Masson, email: [email protected]
Keywords: IKKε, C/EBP-β, IL-6 gene promoter, prostate cancer, cell proliferation
Received: August 26, 2015 Accepted: August 20, 2016 Published: August 26, 2016
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.
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