Survival Mechanism Of Nur77 In Tumor Inflammatory Pathway And The Discovery Of Its New Targeted Drug

TNF-α,as an important pro-inflammatory factor in the tumor microenvironment,can promote malignant proliferation and epithelial-mesenchymal transition in a variety of cancers.In addition,TNF-α has the potential to inhibit tumor cell growth.If we look for the target protein in the TNF-α signaling pathway and transform the tumor-promoting effect of TNF-α into a tumor suppressor effect by regulating the target protein,it will have important theoretical and clinical value.Nur77,an orphan nuclear receptor,is considered to be closely related to cancer,because the expression of Nur77 in cancer cells is higher than normal cells.Therefore,Nur77 is believed to be a good drug target.As an early-stage gene,Nur77 expression is up-regulated after TNF-a stimulation,but the role of Nur77 in TNF-a pathway is still unknown.This study found that Nur77 can compete with PHLPP for binding to AKT,antagonizing the de-phosphorylation of AKT by PHLPP.Thus,Nur77 has the ability to increases AKT/mTORC1 expression by inhibiting the de-phosphorylation process of AKT.And we found that TNF-a can enhance this effect,effectively explaining the pro-cancer effect of inflammatory factors.Therefore,we conclude that TNF-a activates the AKT/mTORC1 pathway through Nur77,which can promote EMT in breast cancer.Moreover,based on the new regulatory mechanism of Nur77α we screened a lead compound NAM446-1.It can directly target Nur77 and effectively relieve the negative regulation of Nur77 on PHLPP-AKT-mTORC1,inhibiting migration and EMT in breast cancer cells.We also demonstrated that NAM446-1 can target Nur77-PHLPP-AKT-mTORC1 regulatory axis and inhibit breast cancer cell proliferation in vivo In summary,this study describes the effect of Nur77 in TNF-a-induced metastasis and EMT in breast cancer cells,and this research can provide a new thought for the development of targeted drugs for Nur77.