Decorin Antagonizes IGF Receptor I (IGF-IR) Function by Interfering with IGF-IR Activity and Attenuating Downstream Signaling
Decorin Antagonizes IGF Receptor I (IGF-IR) Function by Interfering with IGF-IR Activity and Attenuating Downstream Signaling
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DOI：
10.1074/jbc.m111.262766
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发表时间：
2011-10-07
影响因子：
4.8
通讯作者：
Morrione, Andrea
中科院分区：
文献类型：
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作者：
Iozzo, Renato V.;Buraschi, Simone;Morrione, Andrea
我们最近发现胰岛素样生长因子受体I（IGF-IR）在人浸润性膀胱癌中上调，并促进转化的尿路上皮细胞的迁移和侵袭。蛋白多糖核心蛋白聚糖是肿瘤间质的关键成分，可以正向调节正常细胞中的IGF-IR系统。然而，没有关于核心蛋白聚糖在转化细胞或肿瘤模型中调节IGF-IR活性的作用的可用数据。在此，我们发现在低级别和高级别膀胱癌中核心蛋白聚糖的表达与IGF-IR的表达呈负相关（各n = 20）。核心蛋白聚糖在不同的位点与高亲和力的IGF-IR和IGF-I结合，并在尿路上皮癌细胞中负调节IGF-IR活性。纳摩尔浓度的核心蛋白聚糖促进IRS-1（IGF-IR途径的关键蛋白之一）的下调，并减弱IGF-I依赖的Akt和MAPK活化。这导致核心蛋白聚糖诱发的抑制迁移和IGF-I刺激后的入侵。值得注意的是，核心蛋白聚糖没有引起膀胱癌、乳腺癌和鳞状细胞癌细胞中IGF-IR的下调。这表明核心蛋白聚糖对IGF-IR的作用不同于其对其他受体酪氨酸激酶如EGF受体和Met的已知活性。我们的研究结果提供了一个新的机制，核心蛋白聚糖在负性调节IGF-I及其受体。因此，核心蛋白聚糖损失可能有助于增加IGF-IR活性在膀胱癌的进展，也许其他形式的癌症，其中IGF-IR发挥作用。
We have recently discovered that the insulin-like growth factor receptor I (IGF-IR) is up-regulated in human invasive bladder cancer and promotes migration and invasion of transformed urothelial cells. The proteoglycan decorin, a key component of the tumor stroma, can positively regulate the IGF-IR system in normal cells. However, there are no available data on the role of decorin in modulating IGF-IR activity in transformed cells or in tumor models. Here we show that the expression of decorin inversely correlated with IGF-IR expression in low and high grade bladder cancers (n = 20 each). Decorin bound with high affinity IGF-IR and IGF-I at distinct sites and negatively regulated IGF-IR activity in urothelial cancer cells. Nanomolar concentrations of decorin promoted down-regulation of IRS-1, one of the critical proteins of the IGF-IR pathway, and attenuated IGF-I-dependent activation of Akt and MAPK. This led to decorin-evoked inhibition of migration and invasion upon IGF-I stimulation. Notably, decorin did not cause down-regulation of the IGF-IR in bladder, breast, and squamous carcinoma cells. This indicates that decorin action on the IGF-IR differs from its known activity on other receptor tyrosine kinases such as the EGF receptor and Met. Our results provide a novel mechanism for decorin in negatively modulating both IGF-I and its receptor. Thus, decorin loss may contribute to increased IGF-IR activity in the progression of bladder cancer and perhaps other forms of cancer where IGF-IR plays a role.