Identification of an autoregulatory feedback pathway involving interleukin-1α in induction of constitutive NF-κB activation in pancreatic cancer cells
Identification of an autoregulatory feedback pathway involving interleukin-1α in induction of constitutive NF-κB activation in pancreatic cancer cells
复制标题
DOI：
10.1074/jbc.m309789200
复制
发表时间：
2004-04-16
影响因子：
4.8
通讯作者：
Chiao, PJ
中科院分区：
文献类型：
--
作者：
Niu, JG;Li, ZK;Chiao, PJ
我们之前报道过，NF-kappaB 在大多数人胰腺癌组织和细胞系中被组成型激活，但在正常胰腺组织和永生化胰腺导管上皮细胞中却没有被激活。在原位裸鼠模型中，IkappaBalphaM 介导的对人胰腺癌细胞中组成型 NF-kappaB 活性的抑制抑制了肿瘤发生和肝转移，表明组成型 NF-kappaB 激活在胰腺肿瘤进展和转移中发挥着重要作用。然而，NF-κB 在胰腺癌中被激活的潜在机制仍有待阐明。在这项研究中，我们发现自分泌机制解释了转移性人胰腺癌细胞系中 NF-κB 的组成型激活。进一步的研究表明，IL-1α 是这些细胞分泌的激活 NF-κB 的主要细胞因子。在转移性胰腺癌细胞系中，白细胞介素-1α活性的中和抑制了 NF-κB 的组成型激活及其下游靶基因、尿激酶型纤溶酶原激活剂的表达。我们的结果表明，IL-1α 表达的调节主要依赖于 AP-1 活性，而 AP-1 活性部分是由表皮生长因子受体依赖性和非依赖性信号通路诱导的。总之，我们的研究结果表明转移性人胰腺癌细胞中 NF-κB 组成性激活的可能机制以及炎症和癌症之间可能缺失的机制联系。
We previously reported that NF-kappaB is constitutively activated in most human pancreatic cancer tissues and cell lines but not in normal pancreatic tissues and immortalized pancreatic ductal epithelial cells. IkappaBalphaM-mediated inhibition of constitutive NF-kappaB activity in human pancreatic cancer cells suppressed tumorigenesis and liver metastasis in an orthotopic nude mouse model, suggesting that constitutive NF-kappaB activation plays an important role in pancreatic tumor progression and metastasis. However, the underlying mechanism by which NF-kappaB is activated in pancreatic cancer remains to be elucidated. In this study, we found that an autocrine mechanism accounts for the constitutive activation of NF-kappaB in metastatic human pancreatic cancer cell lines. Further investigation showed that interleukin-1alpha was the primary cytokine secreted by these cells that activates NF-kappaB. Neutralization of interleukin-1alpha activity suppressed the constitutive activation of NF-kappaB and the expression of its downstream target gene, urokinase-type plasminogen activator, in metastatic pancreatic cancer cell lines. Our results demonstrate that regulation of interleukin-1alpha expression is primarily dependent on AP-1 activity, which is in part induced by signaling pathways that are epidermal growth factor receptor-dependent and - independent. In conclusion, our findings suggest a possible mechanism for the constitutive activation of NF-kappaB in metastatic human pancreatic cancer cells and a possible missing mechanistic link between inflammation and cancer.