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  • br SM testosterone inhibited the proliferation and metastasi

    2019-10-21


    3.7. SM934-testosterone inhibited the proliferation and metastasis of breast cancer Loxapine Succinate via the downregulation of cathepsin K followed by the suppression of Bcl-xL expression
    To understand the mechanism of action of SM934-Testosterone on the target, pathway enrichment was performed. By KEGG Mapper, we gained five KEGG pathway totally. They are lysosome, rheumatoid ar-thritis, osteoclast differentiation, apoptosis and toll-like receptor sig-naling pathway (Supplementary 5). In apoptosis and toll-like receptor signaling pathway, Cathepsin K appears in the upstream of the whole system, which can affect the expression of all downstream genes and regulate the entire pathway eventually. In the apoptosis pathway (Fig. 7A), Cathepsin K can adjust apoptosis regulator Bcl-X and generate the membrane permeabilization of mitochondrial, which is one of Loxapine Succinate sig-nificant approach of cell apoptosis. In the toll-like receptor signaling pathway, Cathepsin K can affect the downstream targets of toll-like receptors and ultimately induce cell inflammatory response which can affect cell biology process and accelerate cell apoptosis.
    Iwasawa et al. have reported that the expression of Bcl-xL in os-teoblasts and other tissues could be affected by Cathepsin K (Iwasawa and Miyazaki, 2009). Therefore, based on this finding, to further illu-minate the underlying mechanisms of how SM934-Testosterone affect the proliferation and metastasis ability of breast cancer cells MDA-MB-231 and SK-BR-3, the expression level of Bcl-xL protein was analyzed by western blot in different groups, including cells treated with SM934-Testosterone, cells transfected with Cathepsin K shRNA and control cells. We found that the expression of Bcl-xL protein level was de-creased in cells transfected with Cathepsin K shRNA and cells treated with SM934-Testosterone compared with the protein levels in control groups (Fig. 7B–C). Overall, SM934-Testosterone inhibited proliferation and metastasis of MDA-MB-231 cells via suppressing the expression of Cathepsin K, and Cathepsin K reduced the proliferation and metastasis potential of breast cancer cells MDA-MB-231 and SK-BR-3 followed by the suppression of Bcl-xL expression.
    4. Discussion
    Breast cancer is one of the major common cancers worldwide. Surgery, radiation and chemotherapy play influential roles in breast cancer treatment. However, chemoresistance and the high possibility of metastasis are two of the main barriers to cure breast cancer (Akar
    Fig. 4. Computational target prediction.
    (A) The predicted targets Venn diagram of SM934, Testosterone and SM934-Testosterone. (B) The 2D protein-ligand in-teraction diagram between 5DTI and 7AS;
    (C) The 2D protein-ligand interaction dia-gram between 5DTI and SM934-Testosterone; (D) The 2D protein-ligand in-teraction diagram between 5DTI and SM934; (E) The 2D protein-ligand interac-tion diagram between 5DTI and Testosterone. (F) The 3D protein-ligand in-teraction of SM934-testosterone. (G) The surface graph of protein-ligand interaction of SM934-testosterone. The image of this 3D protein-ligand interaction was generated by Pymol program.
    et al., 2008; Zhou et al., 2013). Recently, Chinese traditional medicinal herbs have been considered as sources of novel potential therapeutic drugs for breast cancer. There are around 40% of cancer patients in North America considering Chinese traditional medicine as an adjunct for their treatment (Yin et al., 2013). The derivatives of artemisinin were studied in current research. Artemisinin is extracted from the stems and leaves of Artemisia annua L and is the most important and effective antimalarial drug worldwide. However, as reported, the ac-tivity of artemisinin is not restricted to malaria, artemisinin and its derivatives also reveal bioactivity towards viruses, schistosomiasis, and cancer in vitro and in vivo (Beekman et al., 1998; Lai and Singh, 1995; Rong et al., 2011; Wanxing Eugene et al., 2014). In the present study, the derivative of artemisinin SM934, a novel stable water-soluble ar-temisinin analog, was connected with Testosterone, a 19-carbon ster-oidal compound which has been verified to be related to prostate cancer by covalent bonds. SM934-Testosterone was the production (Fig. 1). The toxicity of SM934, Testosterone, the combination of SM934 and Testosterone, and SM934-Testosterone were detected, and we found that among the three drugs, only SM934-Testosterone could