Transforming growth factor-β1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-κB, JNK, and Ras signaling pathways
Transforming growth factor-β1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-κB, JNK, and Ras signaling pathways
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DOI：
10.1038/sj.onc.1206478
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发表时间：
2003-07-10
期刊：
影响因子：
8
通讯作者：
Chi, SG
中科院分区：
文献类型：
--
作者：
Park, JI;Lee, MG;Chi, SG
转化生长因子（TGF）-β 1作为前列腺上皮细胞的有效生长抑制剂，其I型和II型受体的异常功能与肿瘤侵袭性相关。然而，细胞内和血清TGF-β 1水平在前列腺癌患者中升高，并在转移性癌患者中进一步升高，表明TGF-β 1在前列腺肿瘤发生中的致癌开关作用。最近，我们报道了致癌Ha-Ras在前列腺癌细胞中对TGF-β 1的促有丝分裂转化作用。在这里，我们表明，TGF-β 1激活白细胞介素（IL）-6，这已经牵连到前列腺癌的恶性进展，通过多种信号通路，包括Smad 2，核因子-κ B（NF-κ B），JNK，和Ras。TGF-β 1诱导的IL-6基因表达被DN-Smad 2强烈抑制，但不被DN-Smad 3抑制，而被野生型Smad 2转染进一步激活。TGF-β 1对IL-6的激活伴随着NF-κ B的核转位，这被p38抑制剂SB 202190和SB 203580或IkappaBalphaDeltaN转染阻断，表明p38-NF-κ B信号在TGF-β 1诱导IL-6中的关键作用。TGF-β 1激活c-Jun磷酸化，并且TGF-β 1诱导的IL-6被DN-c-Jun和DN-JNK或AP-1抑制剂姜黄素严重阻碍，表明JNK-c-Jun-AP-1信号传导在TGF-β 1刺激IL-6中起关键作用。还发现Ras-Raf-MEK 1级联被TGF-β 1激活，并以AP-1依赖性方式参与TGF-β 1诱导IL-6。共转染实验表明TGF-β 1刺激IL-6是由Smad 2、p38-NF-kappaB、JNK-c-Jun-AP-1或Ras-Raf-MEK 1级联的协同作用引起的。此外，IL-6衰减的时间过程显示，TGF-β 1适度增加IL-6的mRNA稳定性，表明TGF-β 1也在转录后水平调节IL-6。有趣的是，IL-6失活恢复了对TGF-β 1介导的生长停滞和凋亡的敏感性，这表明晚期前列腺肿瘤中升高的IL-6可能作为TGF-β 1的抵抗因子。总的来说，我们的数据表明，IL-6的表达是刺激肿瘤产生TGF-β 1在人类前列腺癌细胞通过多种信号通路，包括Smad 2，p38，JNK，Ras，和IL-6的表达增强可能有助于致癌开关TGF-β 1的前列腺肿瘤发生的作用，部分通过抵消其生长抑制功能。
Transforming growth factor (TGF)-beta1 acts as a potent growth inhibitor of prostate epithelial cells, and aberrant function of its receptor type I and II correlates with tumor aggressiveness. However, intracellular and serum TGF-beta1 levels are elevated in prostate cancer patients and further increased in patients with metastatic carcinoma, suggesting the oncogenic switch of TGF-beta1 role in prostate tumorigenesis. Recently, we reported the mitogenic conversion of TGF-beta1 effect by oncogenic Ha-Ras in prostate cancer cells. Here, we show that TGF-beta1 activates interleukin (IL)-6, which has been implicated in the malignant progression of prostate cancers, via multiple signaling pathways including Smad2, nuclear factor-kappaB (NF-kappaB), JNK, and Ras. TGF-beta1-induced IL-6 gene expression was strongly inhibited by DN-Smad2 but not by DN-Smad3 while it was further activated by wild-type Smad2 transfection. IL-6 activation by TGF-beta1 was accompanied by nuclear translocation of NF-kappaB, which was blocked by the p38 inhibitors SB202190 and SB203580 or by IkappaBalphaDeltaN transfection, indicating the crucial role for the p38-NF-kappaB signaling in TGF-beta1 induction of IL-6. TGF-beta1 activated c-Jun phosphorylation, and IL-6 induction by TGF-beta1 was severely impeded by DN-c-Jun and DN-JNK or AP-1 inhibitor curcumin, showing that the JNK-c-Jun-AP-1 signaling plays a pivotal role in TGF-beta1 stimulation of IL-6. It was also found that the Ras-Raf-MEK1 cascade is activated by TGF-beta1 and participates in the TGF-beta1 induction of IL-6 in an AP-1-dependent manner. Cotransfection assays demonstrated that TGF-beta1 stimulation of IL-6 results from the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK-c-Jun-AP-1, or Ras-Raf-MEK1 cascades. In addition, a time course IL-6 decay revealed that mRNA stability of IL-6 is modestly increased by TGF-beta1, indicating that TGF-beta1 also regulates IL-6 at the post-transcriptional level. Intriguingly, IL-6 inactivation restored the sensitivity to TGF-beta1-mediated growth arrest and apoptosis, suggesting that elevated IL-6 in advanced prostate tumors might act as a resistance factor against TGF-beta1. Collectively, our data demonstrate that IL-6 expression is stimulated by tumor-producing TGF-beta1 in human prostate cancer cells through multiple signaling pathways including Smad2, p38, JNK, and Ras, and enhanced expression of IL-6 could contribute to the oncogenic switch of TGF-beta1 role for prostate tumorigenesis, in part by counteracting its growth suppression function.