IκB-Kinase-epsilon (IKKε) over-expression promotes the growth of prostate cancer through the C/EBP-β dependent activation of IL-6 gene expression.
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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DOI：
10.18632/oncotarget.11629
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发表时间：
2017-02-28
期刊：
影响因子：
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通讯作者：
Mes-Masson AM
中科院分区：
文献类型：
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作者：
Péant B;Gilbert S;Le Page C;Poisson A;L'Ecuyer E;Boudhraa Z;Bienz MN;Delvoye N;Saad F;Mes-Masson AM
炎性细胞因子IL-6可诱导前列腺癌细胞雄激素受体的核转位，并以非配体依赖的方式激活雄激素受体，提示其可能有助于抗去势表型的形成。血清IL-6水平升高也与前列腺癌患者转移相关的发病率有关。我们先前已经证实，在激素敏感的前列腺癌细胞系中，I-kappa-B-激酶-epsilon(IKKε，又称IKK或IκBKε)过表达可诱导IL-6的分泌。我们还报道了缺乏雄激素受体表达的前列腺癌细胞株表现出高结构性IKKε表达和IL-6分泌。在本研究中，我们验证了IKKε缺失对去势耐药前列腺癌细胞体外增殖的影响，并通过小鼠异种移植的方法研究了IKKε缺失对体内肿瘤生长和IL-6肿瘤分泌的影响。我们观察到，与喂食正常饲料的小鼠相比，注射多西环素补充饲料的SCID小鼠体内注射的IKKε沉默的PC-3细胞的生长明显延迟。我们还发现，IL-6分泌水平的降低与肿瘤生长抑制密切相关。最后，利用含有不同IL-6突变启动子的构建体，我们证明了IKKε的过表达通过激活和核积聚转录因子C/κ-β来诱导非依赖于NF-EBP B的IL-6基因启动子的刺激。我们的研究证实了癌基因IKKε在去势抵抗的前列腺癌细胞系中的促增殖作用，涉及启动IL-6基因表达的C/eBP-β的磷酸化和核转位。
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.