title: Everolimus-induced human keratinocytes toxicity is mediated by STAT3 inhibition.
abstract: BACKGROUND
  Mammalian target of rapamycin (mTOR) inhibitors are associated with dermatological adverse events. The chief aim of this study was to examine the relation between the signal transducer and activator of transcription 3 (STAT3) protein and the dermatological adverse events associated with the mTOR inhibitor everolimus.
  
  
  METHODS
  We evaluated the effects of STAT3 activity and related signal transduction activities on everolimus-induced cell growth inhibition in the human keratinocyte HaCaT cell line via a WST-8 assay, and on signal transduction mechanisms involved in everolimus treatments via a western blot analysis. Apoptosis was evaluated using an imaging cytometric assay.
  
  
  RESULTS
  The cell growth inhibitory effects of everolimus were enhanced by stattic or STA-21, which are selective inhibitors of STAT3, treatment in HaCaT cells, although such effects were not observed in Caki-1 and HepG2 cells. Phosphorylation at tyrosine 705 of STAT3 was decreased by treatment with everolimus in a dose-dependent manner in HaCaT cells; in contrast, phosphorylation at serine 727 was not decreased by everolimus, but slightly increased. Furthermore, we found that pretreatment of p38 MAPK inhibitor and transfection with constitutively active form of STAT3 in HaCaT cells resisted the cytostatic activity of everolimus.
  
  
  CONCLUSIONS
  These findings suggest that STAT3 activity may be a biomarker of everolimus-induced dermatological toxicity.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Uda
authors.forename: Akira
authors.initials: A
authors.lastname: Mukai
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamashita
authors.forename: Manabu
authors.initials: M
authors.lastname: Kume
authors.forename: Hiroo
authors.initials: H
authors.lastname: Makimoto
authors.forename: Toshinori
authors.initials: T
authors.lastname: Bito
authors.forename: Chikako
authors.initials: C
authors.lastname: Nishigori
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirano
authors.forename: Midori
authors.initials: M
authors.lastname: Hirai
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D000068338:Everolimus; D056945:Hep G2 Cells; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000633:toxicity; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; D000068338:Everolimus; D020123:Sirolimus