title: Resveratrol inhibition of human keratinocyte proliferation via SIRT1/ARNT/ERK dependent downregulation of aquaporin 3.
abstract: BACKGROUND
  Aquaporin 3 (AQP3) is the predominant aquaporin in the skin and is overexpressed in hyperplastic epidermal disorders. Upregulation of AQP3 contributes to keratinocyte proliferation and epidermal hyperplasia. Resveratrol, a natural polyphenol, has an anti-proliferative effect on normal human epidermal keratinocytes (NHEKs), but its exact mechanism remains largely unknown.
  
  
  OBJECTIVE
  To investigate the ability and mechanism of resveratrol to affect the proliferation and the AQP3 expression in NHEKs.
  
  
  METHODS
  NHEKs treated with resveratrol were analyzed. BrdU incorporation assay, real-time PCR, Western blotting and RNA interference using small interfering RNA were employed.
  
  
  RESULTS
  At non-toxic concentrations (less than 40μM), resveratrol inhibited the proliferation of NHEKs. Resveratrol inhibited the ERK phosphorylation and the AQP3 expression with reciprocal upregulation of ARNT expression in a concentration-dependent manner. The inhibitory effects of resveratrol on the ERK phosphorylation and the AQP3 expression were canceled by transfection of siRNA for ARNT, but not by that for AhR. Furthermore, the induction effect of resveratrol on ARNT expression was canceled after SIRT1 was knocked down in NHEKs.
  
  
  CONCLUSIONS
  Resveratrol inhibited NHEK proliferation by downregulating the expression of AQP3 in an SIRT1/ARNT/ERK dependent fashion. This novel mechanism may facilitate drug innovation for hyperplastic skin disorders.
authors.affiliation: Department of Dermatology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China; Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Zhouwei
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Research and Clinical Center for Yusho and Dioxin, Kyushu University, Fukuoka, Japan. Electronic address: uchihir@dermatol.med.kyushu-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchi
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Morino-Koga
authors.affiliation: Department of Dermatology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Research and Clinical Center for Yusho and Dioxin, Kyushu University, Fukuoka, Japan.
authors.forename: Masutaka
authors.initials: M
authors.lastname: Furue
mesh_terms: D051400:Aquaporin 3 / Q000235:genetics / Q000378:metabolism*; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D010766:Phosphorylation; D034622:RNA Interference; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D014162:Transfection
chemical_list: C496027:AQP3 protein, human; C497396:ARNT protein, human; D013267:Stilbenes; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051400:Aquaporin 3; D048049:Extracellular Signal-Regulated MAP Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: ARNT; Aquaporin 3; ERK; Keratinocytes; Resveratrol; SIRT1