title: Inhibition of Sonic Hedgehog Signaling Pathway by Thiazole Antibiotic Thiostrepton Attenuates the CD44+/CD24-Stem-Like Population and Sphere-Forming Capacity in Triple-Negative Breast Cancer.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Na
authors.initials: N
authors.lastname: Yang
authors.forename: Tai-Cheng
authors.initials: TC
authors.lastname: Zhou
authors.forename: Xiu-xia
authors.initials: XX
authors.lastname: Lei
authors.forename: Chang
authors.initials: C
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.forename: Zi-Feng
authors.initials: ZF
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Kai-Hua
authors.initials: KH
authors.lastname: Ming
authors.forename: Bi-Cheng
authors.initials: BC
authors.lastname: Wang
authors.forename: Bang-Lao
authors.initials: BL
authors.lastname: Xu
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051927:CD24 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D061986:MCF-7 Cells; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000187:drug effects* / Q000378:metabolism; D013883:Thiostrepton / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D053823:Hedgehog Proteins; D018960:Hyaluronan Receptors; D013883:Thiostrepton