Abstract:
:Breast cancer is one of the main diagnosis cancers annually worldwide. It is difficult to thorough cure due to drug resistance and the high possibility of metastasis. SM934 is a novel water-soluble artemisinin analog, and has been reported to have a promising therapeutic effect on multiple autoimmune diseases. In this study, SM934 was combined with Testosterone, which is related to prostate cancer, and the reaction product was SM934-Testosterone. We aimed to explore whether SM934, Testosterone and SM934-Testosterone could inhibit tumorigenesis and metastasis of breast cancer cells. Moreover, the mechanism also remains to be clarified. The results of our study showed that among the three compounds, only SM934-Testosterone treatment could lead to the suppression of cell proliferation and metastasis with IC50 = 30.66 ± 2.13 μM at 24 h in MDA-MB-231 and IC50 = 31.11 ± 1.79 μM at 24 h in SK-BR-3, where apoptosis was induced. But SM934-Testosterone showed little effects on breast cancer in vivo due to its poor water-solubility. Furthermore, computational target prediction and experimental validation demonstrated that Cathepsin K was the target of SM934-Testosterone. SM934-Testosterone inhibited the expression of Cathepsin K in breast cancer cells. Then, down-regulation of Cathepsin K in cancer cells by transfected with Cathepsin K shRNA inhibited cell 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.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Gu X,Peng Y,Zhao Y,Liang X,Tang Y,Liu Jdoi
10.1016/j.ejphar.2019.05.011subject
Has Abstractpub_date
2019-09-05 00:00:00pages
172382eissn
0014-2999issn
1879-0712pii
S0014-2999(19)30315-2journal_volume
858pub_type
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