Previous studies have demonstrated that insulin-like growth factor-I (IGF-1) and reactive oxygen species (ROS) are involved in the development and progression of various cancers. However, their regulatory mechanism remains unknown. In this study, we treated cancer cells (HeLa, HepG2 and SW1116 cells) and normal cells (NCM-460) with IGF-1 at different concentrations and for different times and found that cancer cells produced large amounts of cytoplasmic ROS in cancer cells but not in normal cells. Further mechanistic analysis demonstrated that IGF-1 activated NFκB and NLRP3 inflammatory signalling in HeLa cells; systematic analysis indicated that IGF-1 activates NFκB and NLRP3, and the activation was cytosolic ROS- and NADPH oxidase 2 (NOX2)-dependent. Additionally, through coimmunoprecipitation experiments, we found that the IRS-1/COX2/mPGES-1/MAPKs/RAC2/NOX2 pathway nexus was involved in IGF-1-induced NFκB and NLRP3 production. Finally, we validated the regulatory mechanisms through IRS-1, mPGES-1 or NOX2 inhibition using their respective selective inhibitors or shRNA knockdown. Taken together, this is the first report on the mechanism by which IGF-1 activates NFκB and NLRP3 inflammatory signalling via ROS. These findings pave the way for an in-depth study of the role of IGF-1 and ROS in inflammation associated with the development and progression of cancer.

中文翻译：

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胰岛素样生长因子-I 通过癌细胞中的 ROS 激活 NFκB 和 NLRP3 炎症信号。


此前的研究表明，胰岛素样生长因子-I (IGF-1) 和活性氧 (ROS) 参与多种癌症的发生和进展。然而，它们的调节机制仍然未知。在这项研究中，我们用不同浓度和不同时间的IGF-1处理癌细胞（HeLa、HepG2和SW1116细胞）和正常细胞（NCM-460），发现癌细胞在癌细胞中产生大量细胞质ROS，但正常细胞中不存在。进一步的机制分析表明IGF-1激活HeLa细胞中的NFκB和NLRP3炎症信号传导；系统分析表明，IGF-1 激活 NFκB 和 NLRP3，且该激活依赖于胞质 ROS 和 NADPH 氧化酶 2 (NOX2)。此外，通过免疫共沉淀实验，我们发现IRS-1/COX2/mPGES-1/MAPKs/RAC2/NOX2通路关系参与了IGF-1诱导的NFκB和NLRP3的产生。最后，我们通过使用各自的选择性抑制剂或 shRNA 敲低来抑制 IRS-1、mPGES-1 或 NOX2 来验证调节机制。总而言之，这是关于 IGF-1 通过 ROS 激活 NFκB 和 NLRP3 炎症信号传导机制的第一份报告。这些发现为深入研究 IGF-1 和 ROS 在与癌症发生和进展相关的炎症中的作用铺平了道路。