A Novel Derivative Of Artemisinin Inhibits Cell Proliferation And Metastasis Via Down-regulation Of Cathepsin K In Breast Cancer

Breast cancer is one of the major common cancers worldwide.Surgery,radiation and chemotherapies are the three main therapies for breast cancer.But it is difficult to thorough cure due to drug resistance and the high possibility of metastasis.Based on this,new therapeutic drugs need to be developed to relieve patients'clinical symptoms,and extend their survival time.SM934 is a novel water-soluble artemisinin analog which has been reported to have a promising therapeutic effect on multiple autoimmune diseases,but few studies have investigated its functional effects on cancers.In this study,testosterone,retinoic acid and SM934 were linked by covalent bond,and the new compounds SM934-testosterone and SM934-retinoic acid were obtained.The experimental study of SM934,testosterone,retinoic acid,SM934 combined with testosterone,SM934 combined with retinoic acid and the two novel compounds were studied on breast cancer cells.The results showed that in all the experimental groups,only the SM934-testosterone-treated group could lead to the suppression of cell proliferation and metastasis with IC50 =30.66 ± 2.13 ?M at 24 hours in MDA-MB-231 and IC50?31.11±1.79 ?M at 24 hours in MDA-MB-231 where apoptosis was induced.In addition,computational target prediction demonstrated that Cathepsin K was the target of SM934-Testosterone and experiments confirmed that SM934-testosterone inhibited the expression of Cathepsin K in breast cancer cells.Studies have shown that Cathepsin K is highly expressed in breast cancer,so the shRNA of Cathepsin K was constructed to confirm the role of Cathepsin K in the proliferation and metastasis of breast cancer cells.Moreover,pathway enrichment was performed to understand the mechanism of action that Cathepsin K could adjust apoptosis regulator Bcl-X,and knockdown of Cathepsin K by SM934-Testosterone resulted in the reduction of Bcl-xL,which has been reported to be related to the proliferation and metastasis of cells.Collectively,SM934-Testosterone inhibited proliferation and metastasis ability of breast cancer cells via inhibiting the expression of Cathepsin K followed by the inhibition of Bcl-xL.