Insulin-like growth factor-I activates NFκB and NLRP3 inflammatory signalling via ROS in cancer cells.

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.

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Declaration of competing interest All the authors have approved the manuscript and agree with submission to your esteemed journal. There are no conflicts of interest to declare.