| Homoharringtonine(HHT)is an alkaloid with anti-tumor activities,which has a good therapeutic effect on chronic myeloid leukemia.It is equally effective in CML patients resistant to tyrosine kinase inhibitors,but useless for solid tumors.Tamoxifen(TAM)is the first line drug for the treatment of ER-positive breast cancer which almost 70%of breast cancer belongs to.However,during the treatment process,almost 40%of patients will be resistant to TAM,which leads to the failure of the treatment and that becomes a great obstacle for the treatment of ER-positive breast cancer.There are significant differences in the expression and function of the orphan nuclear receptor Nur77 in different tumor cells,and many studies have confirmed the importance of Nur77 in drug resistance of a variety of diseases.In this study,we mainly explored the role and mechanism of Nur77 in HHT-treated solid tumor cells and TAM-treated ER-positive breast cancer cells.In our study,we found that in non-small lung cancer NCI-H292 cells,HHT may induce the expression of Nur77 and promote the interaction between Nur77 and Rictor,a key protein of mTORC2,thereby regulating the function of mTORC2 and activating the AKT signaling pathway,which in turn leads to resistance to HHT-induced apoptosis.Therefore,this may be an important factor for the poor efficacy of HHT and other drugs in some solid tumors.In ER-positive breast cancer MCF-7 cells,TAM also induces the expression of Nur77,which may counteract the pro-apoptotic effect of TAM by inhibiting the activation of the p38 signaling pathway and inducing the expression of the pro-survival protein Bcl-2.High expression of Nur77 in TAM-resistant MCF-7/LCC 2 cells may be one of the important factors for its resistance.Further more,small molecular compounds targeting Nur77 were identified in NCI-H292 cells and MCF-7/LCC2 cells,providing a basis for the treatment of drug-resistant diseases through combination drug therapy. |
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