title: HSF1 overexpression enhances oncolytic effect of replicative adenovirus.
abstract: BACKGROUND
  E1B55kD deleted oncolytic adenovirus was designed to achieve cancer-specific cytotoxicity, but showed limitations in clinical study. To find a method to increase its efficacy, we investigated the correlation between oncolytic effect of such oncolytic adenovirus Adel55 and intracellular heat shock transcription factor 1 (HSF1) activity.
  
  
  METHODS
  In the present study, human breast cancer cell line Bcap37 was stably transfected with constitutively active HSF1 (cHSF1) or HSF1 specific siRNA (HSF1i) to establish increased or decreased HSF1 expression levels. Cytotoxicity of Adel55 was analyzed in these cell lines in vitro and in vivo. Furthermore, Adel55 incorporated with cHSF1 (Adel55-cHSF1) was used to treat various tumor xenografts.
  
  
  RESULTS
  Adel55 could achieve more efficient oncolysis in cHSF1 transfected Bcap37 cells, both in vitro and in vivo. However, inhibition of HSF1 expression by HSF1i could rescue Bcap37 cell line from oncolysis by Adel55. A time course study of viral replication established a correlation between higher replication of Adel55 and cytolysis or tumor growth inhibition. Then, we constructed Adel55-cHSF1 for tumor gene therapy and demonstrated that it is more potent than Adel55 itself in oncolysis and replication in both Bcap37 and SW620 xenografts.
  
  
  CONCLUSIONS
  cHSF1 enhances the Adel55 cell-killing potential through increasing the viral replication and is a potential therapeutic implication to augment the potential of E1B55kD deleted oncolytic adenovirus by increasing its burst.
authors.affiliation: Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.forename: Zhehao
authors.initials: Z
authors.lastname: Dai
authors.forename: Rong
authors.initials: R
authors.lastname: Fan
authors.forename: Youwen
authors.initials: Y
authors.lastname: Deng
authors.forename: Guohua
authors.initials: G
authors.lastname: Lv
authors.forename: Guangxiu
authors.initials: G
authors.lastname: Lu
mesh_terms: D000256:Adenoviridae / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D003588:Cytopathogenic Effect, Viral / Q000276:immunology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D000076249:Heat Shock Transcription Factors; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000502:physiology*; D000091402:Prohibitins; D014157:Transcription Factors / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; C000717331:PHB2 protein, human; C000717333:Phb2 protein, mouse; D000091402:Prohibitins; D014157:Transcription Factors
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