LNCaP prostate cancer cells with autocrine interleukin-6 expression are resistant to IL-6-induced neuroendocrine differentiation due to increased expression of suppressors of cytokine signaling
LNCaP prostate cancer cells with autocrine interleukin-6 expression are resistant to IL-6-induced neuroendocrine differentiation due to increased expression of suppressors of cytokine signaling
复制标题
DOI：
10.1002/pros.22479
复制
发表时间：
2012-09-01
期刊：
影响因子：
2.8
通讯作者：
You, Zongbing
中科院分区：
文献类型：
--
作者：
Ge, Dongxia;Gao, Allen C.;You, Zongbing
背景：神经内分泌分化（NED）是去势抵抗性前列腺癌（CRPC）发生的机制之一。在这项研究中，我们研究了IL-6诱导的NED在两个LNCaP亚系。方法以分泌IL-6的LNCaP亚系LNCaP-S17和不表达IL-6的对照亚系LNCaP-C3为研究对象，分析IL-6诱导的NED、JAK 2和STAT 3通路的激活、IL-6/IL-6 R信号转导蛋白和下游靶基因的表达。结果IL-6在LNCaP-C3细胞中诱导NED，但在LNCaP-S17细胞中不诱导NED。IL-6在LNCaP-C3细胞中激活JAK 2和STAT 3通路，但在LNCaP-S17细胞中不激活。IL-6不激活ERK 1/2、AKT或NF-？B途径。LNCaP-C3和LNCaP-S17细胞系均以几乎相同的水平表达IL-6 R、gp 130和TYK 2，并且不表达JAK 1或JAK 3。JAK 2在LNCaP-C3细胞中的基础表达水平略高于LNCaP-S17细胞。细胞因子信号传导的两个抑制因子SOCS 7和烟碱诱导的SH 2蛋白（CIS）在LNCaP-S17细胞中的组成型表达水平高于LNCaP-C3细胞，而SOCS 1至SOCS 6的表达水平大致相同。使用SiRNA敲低LNCaP-S17细胞中SOCS 7和CIS的表达，导致IL-6刺激后STAT 3的磷酸化增加。结论LNCaP-S17细胞对外源性IL-6诱导的NED具有抵抗性，这是由于CIS/SOCS 7水平升高，阻断JAK 2-STAT 3通路的激活。前列腺72：13061316，2012。(c)2011 Wiley Periodicals，Inc.
BACKGROUND Neuroendocrine differentiation (NED) is one of the mechanisms underlying development of castration-resistant prostate cancer (CRPC). In this study, we investigated IL-6-induced NED in two LNCaP sublines. METHODS LNCaP-S17, an LNCaP subline that secretes IL-6, and LNCaP-C3, a control subline that does not express IL-6, were analyzed for IL-6-induced NED, activation of JAK2 and STAT3 pathways, and expression of IL-6/IL-6R signaling proteins and downstream target genes. RESULTS IL-6 did not induce NED in LNCaP-S17 cells, even though IL-6 induced NED in LNCaP-C3 cells. IL-6 activated JAK2 and STAT3 pathways in LNCaP-C3 cells but not in LNCaP-S17 cells. IL-6 did not activate ERK1/2, AKT, or NF-?B pathways in either cell line. Both LNCaP-C3 and LNCaP-S17 cell lines expressed IL-6R, gp130, and TYK2 at almost the same levels and did not express JAK1 or JAK3. The basal level of JAK2 expression was slightly higher in LNCaP-C3 cells than in LNCaP-S17 cells. Two suppressors of cytokine signaling, SOCS7 and cytokine-inducible SH2 protein (CIS), were expressed constitutively at higher levels in LNCaP-S17 cells than in LNCaP-C3 cells, while SOCS1 to SOCS6 were expressed at approximately the same levels. Using siRNA to knockdown SOCS7 and CIS expression in LNCaP-S17 cells led to increased phosphorylation of STAT3 upon IL-6 stimulation. CONCLUSIONS LNCaP-S17 cells are resistant to exogenous IL-6-induced NED due to increased levels of CIS/SOCS7 that block activation of JAK2-STAT3 pathways. Prostate 72:13061316, 2012. (c) 2011 Wiley Periodicals, Inc.