title: A selenosemicarbazone complex with copper efficiently down-regulates the 90-kDa heat shock protein HSP90AA1 and its client proteins in cancer cells.
abstract: BACKGROUND
  The 90-kDa heat shock protein HSP90AA1 is critical for the stability of several proteins that are important for tumor progression and thus, is a promising target for cancer therapy. Selenosemicarbazone metal complexes have been shown to possess anticancer activity through an unknown molecular mechanism.
  
  
  METHODS
  The MTT assay, fluorescence-activated cell sorting, and fluorescent microscopy were used to analyze the mechanism of the anti-cancer activity of the selenosemicarbazone metal complexes. Additionally, RNA-seq was applied to identify transcriptional gene changes, and in turn, the signaling pathways involved in the process of 2-24a/Cu-induced cell death. Last, the expression of HSP90AA1, HSPA1A, PIM1, and AKT proteins in 2-24a/Cu-treated cells were investigated by western blot analysis.
  
  
  RESULTS
  A novel selenosemicarbazone copper complex (2-24a/Cu) efficiently induced G2/M arrest and was cytotoxic in cancer cells. 2-24a/Cu significantly induced oxidative stress in cancer cells. Interestingly, although RNA-seq revealed that the transcription of HSP90AA1 was increased in 2-24a/Cu-treated cells, western blotting showed that the expression of HSP90AA1 protein was significantly decreased in these cells. Furthermore, down-regulation of HSP90AA1 led to the degradation of its client proteins (PIM1 and AKT1), which are also cancer therapy targets.
  
  
  CONCLUSIONS
  Our results showed that 2-24a/Cu efficiently generates oxidative stress and down-regulates HSP90AA1 and its client proteins (PIM1, AKT1) in U2os and HeLa cells. These results demonstrate the potential application of this novel copper complex in cancer therapy.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Shen
authors.forename: Haichuan
authors.initials: H
authors.lastname: Zhu
authors.forename: Mowei
authors.initials: M
authors.lastname: Song
authors.forename: Yonglu
authors.initials: Y
authors.lastname: Tian
authors.forename: Yafei
authors.initials: Y
authors.lastname: Huang
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Ruiyuan
authors.initials: R
authors.lastname: Cao
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.affiliation: The First Affiliated Hospital of Harbin Medical University, Harbin, China. drbizhenggang@163.com.
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Bi
authors.forename: Wu
authors.initials: W
authors.lastname: Zhong
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D016566:Organoselenium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D012510:Sarcoma 180 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C000598121:(di-2-pyridyl ketone-4,4-dimethyl-3-selenosemicarbazide)copper(II); D056831:Coordination Complexes; D018841:HSP90 Heat-Shock Proteins; D016566:Organoselenium Compounds; D003300:Copper; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1