Androgen receptor signaling: Mechanism of interleukin-6 inhibition
Androgen receptor signaling: Mechanism of interleukin-6 inhibition
复制标题
DOI：
10.1158/0008-5472.can-03-3486
复制
发表时间：
2004-04-01
期刊：
影响因子：
11.2
通讯作者：
Coetzee, GA
中科院分区：
文献类型：
--
作者：
Jia, L;Choong, CSY;Coetzee, GA
通过雄激素受体（AR）的非甾体信号传导在难治性前列腺癌中起着重要作用。先前，我们已经报道了多效性细胞因子白细胞介素（IL）-6抑制LNCaP细胞中二氢睾酮介导的前列腺特异性抗原的表达（Jia et al.，Mol Can Res 2003; 1：385 - 92）。在本研究中，我们探讨了这种抑制作用的机制，并考虑了对AR核转位、转录辅因子的募集以及可能介导这种抑制作用的信号通路的可能影响。IL-6既不诱导AR的核定位，也不抑制二氢睾酮诱导的受体核转位。IL-6不影响AR或p160共激活因子在前列腺特异性抗原增强子和启动子上的转录起始复合物的募集。此外，它没有导致招募辅阻遏物沉默介质的维甲酸和甲状腺激素受体（SMRT）或组蛋白脱乙酰酶1（HDAC 1）在相同的网站。然而，IL-6确实阻止了次级共激活因子p300向复合物的募集，并部分抑制了相同位点的组蛋白H3乙酰化。此外，IL-6的抑制作用不是由促分裂原活化蛋白激酶或Akt通路介导的，并且通过使用小干扰RNA敲低转录-3的信号转导子和激活子而被部分废除。我们的研究结果表明，IL-6调节雄激素的作用，通过差异募集辅因子的靶基因。这些发现可能解释了IL-6在恶性前列腺细胞中的多效性作用。
Nonsteroidal signaling via the androgen receptor (AR) plays an important role in hormone-refractory prostate cancer. Previously, we have reported that the pleiotropic cytokine, interleukin (IL)-6, inhibited dihydrotestosterone-mediated expression of prostate-specific antigen in LNCaP cells (Jia et al., Mol Can Res 2003;1:385-92). In the present study, we explored the mechanisms involved in this inhibition and considered possible effects on AR nuclear translocation, recruitment of transcription cofactors, and the signaling pathways that may mediate this inhibitory effect. IL-6 neither induced nuclear localization of the AR nor inhibited dihydrotestosterone-induced nuclear translocation of the receptor. IL-6 did not affect AR or p160 coactivator recruitment to the transcription initiation complex on the prostate-specific antigen enhancer and promoter. Moreover, it did not lead to the recruitment of the corepressor silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) or histone deacetylase 1 (HDAC1) at the same sites. IL-6 did, however, prevent the recruitment of the secondary coactivator, p300, to the complex and partially inhibited histone H3 acetylation at the same loci. Furthermore, inhibition by IL-6 was not mediated by the mitogen-activated protein kinase or the Akt pathways and was partially abrogated by signal transducers and activators of transcription-3 knock-down using small interfering RNA. Our results show that IL-6 modulates androgen action through the differential recruitment of cofactors to target genes. These findings may account for the pleiotropic actions of IL-6 in malignant prostate cells.