期刊
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
卷 38, 期 3, 页码 1157-1170出版社
KARGER
DOI: 10.1159/000443066
关键词
Thiostrepton; Triple-negative breast cancer; Sonic hedgehog; Breast cancer stem cell
资金
- National Basic Research Program of China (973 Program) [2012CB967000]
- Sister Institution Network Fund (SINF)
- National Natural Science Foundation of China [81130040]
Background/Aim: Triple-negative breast cancer (TNBC) represents a particular clinical challenge because these cancers do not respond to endocrine therapy or other available targeted agents. The lack of effective agents and obvious targets are major challenges in treating TNBC. In this study we explored the cytostatic effect of thiazole ring containing antibiotic drug thiostrepton on TNBC cell lines and investigated the molecular mechanism. Methods: Cell viability was measured by MTT assay. Cell surface marker was monitored by FCM. Western blot was applied to assess the protein expression levels of target genes. Results: We found that thiostrepton remarkably suppressed the CD44+/CD24-stem-like population and sphere forming capacity of TNBC cell lines. Notably, we showed for the first time that thiostrepton exerted its pharmacological action by targeting sonic hedgehog (SHH) signaling pathway. Thiostrepton repressed SHH ligand expression and reduced Gli-1 nuclear localization in TNBC cell line. Furthermore, the downstream target of SHH signaling undergone dose-dependent, rapid, and sustained loss of mRNA transcript level after thiostrepton treatment. Finally, we showed that SHH ligand was essential for maintaining CD44+/CD24-stem-like population in TNBC cell line. Conclusion: We conclude that thiostrepton suppresses the CD44+/CD24-stem-like population through inhibition of SHH signaling pathway. Our results give a new insight into the mechanism of thiostrepton anti-tumor activity and suggest thiostrepton as a promising agent that targets hedgehog signaling pathway in TNBC. (C) 2016 The Author(s) Published by S. Karger AG, Basel
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