Resveratrol inhibition of human keratinocyte proliferation via SIRT1/ARNT/ERK dependent downregulation of aquaporin 3
Resveratrol inhibition of human keratinocyte proliferation via SIRT1/ARNT/ERK dependent downregulation of aquaporin 3
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DOI：
10.1016/j.jdermsci.2014.03.004
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发表时间：
2014-07-01
影响因子：
4.6
通讯作者：
Furue, Masutaka
中科院分区：
文献类型：
--
作者：
Wu, Zhouwei;Uchi, Hiroshi;Furue, Masutaka
背景：水通道蛋白3（AQP 3）是皮肤中主要的水通道蛋白，在增生性表皮疾病中过表达。AQP 3的上调有助于角质形成细胞增殖和表皮增生。白藜芦醇（Resveratrol）是一种天然多酚类物质，对正常人表皮角质形成细胞（human epidermal keratinocytes，NHEK）具有抗增殖作用，但其确切机制尚不清楚。目的：探讨白藜芦醇对NHEK增殖及水通道蛋白3（AQP 3）表达的影响。采用BrdU掺入法、实时荧光定量PCR、Western blotting和小分子干扰RNA（siRNA）技术检测白藜芦醇对NHEKs增殖的抑制作用。白藜芦醇以浓度依赖性方式抑制ERK磷酸化和AQP 3表达，并相互上调ARNT表达。白藜芦醇对ERK磷酸化和AQP 3表达的抑制作用可被转染ARNT的siRNA所抵消，但不能被转染AhR的siRNA所抵消。结论：白藜芦醇通过下调AQP 3的表达来抑制NHEK的增殖，其抑制作用与SIRT 1/ARNT/ERK依赖性有关。这种新的机制可能有助于增生性皮肤病的药物创新。(C)2014年日本皮肤病研究学会。由Elsevier爱尔兰有限公司出版。保留所有权利。
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 40 mu M), 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.Conclusion: 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. (C) 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.