Interleukin-8 signaling promotes androgen-independent proliferation of prostate cancer cells via induction of androgen receptor expression and activation
Interleukin-8 signaling promotes androgen-independent proliferation of prostate cancer cells via induction of androgen receptor expression and activation
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DOI：
10.1093/carcin/bgn109
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发表时间：
2008-06-01
期刊：
影响因子：
4.7
通讯作者：
Waugh, David J. J.
中科院分区：
文献类型：
--
作者：
Seaton, Angela;Scullin, Paula;Waugh, David J. J.
本研究的目的是评估CXC趋化因子和白细胞介素（IL）-8在促进前列腺癌（CaP）向雄激素非依赖性状态转变中的重要性。外源性重组人白细胞介素-8（rh-IL-8）刺激雄激素依赖性细胞系LNCaP和22 Rv 1，分别通过定量聚合酶链反应和免疫印迹法评估，在信使RNA（mRNA）和蛋白水平上增加雄激素受体（AR）基因表达。使用雄激素反应元件-荧光素酶构建体，我们证明了rh-IL-8处理也导致这两种细胞系中AR转录活性增加，以及随后LNCaP细胞中前列腺特异性抗原和细胞周期蛋白依赖性激酶2 mRNA转录水平上调。使用小分子拮抗剂（AZ 10397767）阻断CXC趋化因子受体-2信号传导减弱了IL-8诱导的AR表达和转录活性增加。此外，在3-（4，5-二甲基噻唑-2-基）-2，5-二苯基四唑溴化物试验中，AZ 10397767联合给药降低了暴露于比卡鲁胺的LNCaP和22 Rv 1细胞的活力。我们的数据表明，IL-8信号增加AR的表达，并促进配体非依赖性激活该受体在两个雄激素依赖性细胞系，描述了两种机制，这种趋化因子可能有助于促进钙磷过渡到雄激素非依赖性状态。此外，我们的数据表明，IL-8促进的AR调节减弱了AR拮抗剂比卡鲁胺降低CaP细胞活力的有效性。
The aim of our study was to assess the importance of the CXC chemokine and interleukin (IL)-8 in promoting the transition of prostate cancer (CaP) to the androgen-independent state. Stimulation of the androgen-dependent cell lines, LNCaP and 22Rv1, with exogenous recombinant human interleukin-8 (rh-IL-8) increased androgen receptor (AR) gene expression at the messenger RNA (mRNA) and protein level, assessed by quantitative polymerase chain reaction and immunoblotting, respectively. Using an androgen response element-luciferase construct, we demonstrated that rh-IL-8 treatment also resulted in increased AR transcriptional activity in both these cell lines, and a subsequent upregulation of prostate-specific antigen and cyclin-dependent kinase 2 mRNA transcript levels in LNCaP cells. Blockade of CXC chemokine receptor-2 signaling using a small molecule antagonist (AZ10397767) attenuated the IL-8-induced increases in AR expression and transcriptional activity. Furthermore, in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, coadministration of AZ10397767 reduced the viability of LNCaP and 22Rv1 cells exposed to bicalutamide. Our data show that IL-8 signaling increases AR expression and promotes ligand-independent activation of this receptor in two androgen-dependent cell lines, describing two mechanisms by which this chemokine may assist in promoting the transition of CaP to the androgen-independent state. In addition, our data show that IL-8-promoted regulation of the AR attenuates the effectiveness of the AR antagonist bicalutamide in reducing CaP cell viability.