Glibenclamide Inhibits Growth Of Non-small Cell Lung Cancer By Targeting SUR1 To Regulate P70S6K Signaling Pathway

Lung cancer is the most common cancer in the world,and its morbidity and mortality are the highest in china.Early screening and treatment results in better prognosis;however,the majority of clinically diagnosed patients belong to the middle and late stage.Therefore,it is particularly important to clarify the progress of the diseases and identify new targets for cancer therapy.Glibenclamide is a traditional oral antidiabetic drug.It showed anticancer effects in some types of cancer cells.However,for its effects and mechanism in non-small cell lung cancer are still unclear.Sulfonyurea receptor 1?SUR1?is the receptor of glibenclamide,and is the regulatory subunit of the K_ATP channels.The binding of SUR1 with glibenclamide induced the closure of K_ATP channels and secretiong of insulin in islet?cells.For its expression and function in cancer is quite unknown.In this study,we found that glibenclamide induced growth inhibition of non-small cell lung cancer cells and cell cycle arrest at G₁ phase,in parallele with inhibition of p70S6K.Knockdown of SUR1 expression suppressed cell growth and downregulated p70S6K signaling pathway,which was consistent with glibenclmide's effect.However,overexpression of SUR1 promoted cells growth and activated p70S6K.Moreover,overexpression of p70S6K partially abolishes the growth inhibitory effects of glibenclamide,whereas knockdown of p70S6K expression enhances the effect of glibenclamide.Furthermore,p70S6K physically bound to SUR1,and glibenclamide enhanced their binding.Meanwhile,glibenclamide abrogated mTORC1.These may result in the inhibition of p70S6K signaling pathway.In nude mouse xenograft model,we found that glibenclamide or stable silencing of SUR1 expression suppressed the growth of A549 tumors and downregulated p70S6K signaling.Finally,we analysed the Oncomine and Kaplan survival database and found that the expression of SUR1 increased in lung cancer patients and higher expression levels of SUR1 was correlated with poor survival rate.In this study,we clarified that glibenclamide targets SUR1 to inhibit p70S6K signaling pathway through enchancing the binding of SUR1 with p70S6K and abrogating mTORC1,and suppress the growth of non-small cell lung cancer.These findings provide theoretical and experimental evidence for targeting SUR1 or the use of antidiabetic drugs for the treatment of non-small cell lung cancer.