Li Shun, Pinard Maxime, Wang Yunling, Yang Long, Lin Rongtuan, Hiscott John, Su Bing, Brodt Pnina
Dept of Medicine, McGill University and the McGill University Health Center, Canada.
Dept of Surgery, McGill University and the McGill University Health Center, Canada.
Growth Horm IGF Res. 2015 Oct;25(5):253-61. doi: 10.1016/j.ghir.2015.07.008. Epub 2015 Jul 20.
The receptor for type I insulin like growth factor (IGF-IR) and NFκB signaling both play essential roles in cancer initiation and progression but relatively little is known about possible crosstalk between these pathways. We have shown that the IGF-IR could rescue lung and colon carcinoma cells from Tumor necrosis factor -α (ΤΝF-α)-induced apoptosis by activating autocrine, pro-survival IL-6/gp130/STAT3 signaling, suggesting that IGF-IR expression could alter NF-κB signaling that is required for transcriptional activation of IL-6.
Here we sought to determine if and how IGF-IR signaling promotes TNF-α-induced NFκB activation.
We used lung carcinoma M-27 and colon carcinoma MC-38 cells to investigate IGF-IR-induced changes to the IKK/IκBα/NFκB pathway by a combination of qPCR, Western blotting, electrophoretic mobility shift assay, a reporter assay and gene silencing.
We show that in the presence of increased IGF-IR expression or activation levels, nuclear translocation of NFκB in response to TNF-α was enhanced in lung and colon carcinoma cells and this was due to accelerated phosphorylation and degradation of IκBα. This effect was AKT-dependent and mediated via mitogen-activated protein kinase kinase kinase 3(MEKK3) activation.
The results suggest that ligand-mediated activation of IGF-IR alters NF-κB signaling in cancer cells in an AKT/MEKK3-dependent manner and that temporal aspects of NF-κB activation can regulate the cytokine profile of the tumor cells and thereby, their interaction with the microenvironment.
I型胰岛素样生长因子受体（IGF-IR）和NFκB信号通路在癌症的发生和发展中均起着至关重要的作用，但对于这些通路之间可能存在的相互作用却知之甚少。我们已经表明，IGF-IR可以通过激活自分泌的、促生存的IL-6/gp130/STAT3信号通路，使肺癌和结肠癌细胞免受肿瘤坏死因子-α（TNF-α）诱导的凋亡，这表明IGF-IR的表达可能会改变IL-6转录激活所需的NF-κB信号通路。
在此，我们试图确定IGF-IR信号通路是否以及如何促进TNF-α诱导的NFκB激活。
我们使用肺癌M-27细胞和结肠癌MC-38细胞，通过定量聚合酶链反应、蛋白质免疫印迹法、电泳迁移率变动分析、报告基因检测和基因沉默等方法，研究IGF-IR诱导的IKK/IκBα/NFκB信号通路的变化。
我们发现，在IGF-IR表达或激活水平升高的情况下，肺癌和结肠癌细胞中响应TNF-α的NFκB核转位增强，这是由于IκBα的磷酸化和降解加速所致。这种效应依赖于AKT，并通过丝裂原活化蛋白激酶激酶激酶3（MEKK3）的激活介导。
结果表明，配体介导的IGF-IR激活以AKT/MEKK3依赖的方式改变癌细胞中的NF-κB信号通路，并且NFκB激活的时间方面可以调节肿瘤细胞的细胞因子谱，从而调节它们与微环境的相互作用。
