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Cigarette Smoke Induces Cellular Senescence via Werner's Syndrome Protein Down-regulation

¹ Division of Pulmonary, Critical Care, and Occupational Medicine, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, ² Veterans Administration Medical Center, ³ Department of Microbiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, and ⁴ Free Radical and Radiation Biology Program, Department of Radiation Oncology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and ⁵ Department of Pathology, University of Washington, Seattle, Washington

Correspondence and requests for reprints should be addressed to Toru Nyunoya, M.D., Division of Pulmonary, Critical Care, and Occupational Medicine, EMRB 100, Iowa City, IA 52242. E-mail: toru-nyunoya{at}uiowa.edu

Rationale: Werner's syndrome is a genetic disorder that causes premature aging due to loss-of-function mutations in a gene encoding a member of the RecQ helicase family. Both Werner's syndrome and cigarette smoking accelerate aging. No studies have examined the effect of cigarette smoke on Werner's syndrome protein.

Objectives: To investigate the role of Werner's syndrome protein in cigarette smoke–induced cellular senescence.

Methods: Cellular senescence and amounts of Werner's syndrome protein were measured in fibroblasts isolated from patients with emphysema and compared with age-matched nonsmokers. The in vitro effects of cigarette smoke on amounts of Werner's syndrome protein, function, and senescence were also evaluated in primary human lung fibroblasts and epithelial cells.

Measurements and Main Results: Cultured lung fibroblasts isolated from patients with emphysema exhibited a senescent phenotype accompanied by a decrease in Werner's syndrome protein. Cigarette smoke extract decreased Werner's syndrome protein in cultured fibroblasts and epithelial cells. Werner's syndrome protein–deficient fibroblasts were more susceptible to cigarette smoke–induced cellular senescence and cell migration impairment. In contrast, exogenous overexpression of Werner's syndrome protein attenuated the cigarette smoke effects.

Conclusions: Cigarette smoke induces cellular senescence and cell migration impairment via Werner's syndrome protein down-regulation. Rescue of Werner's syndrome protein down-regulation may represent a potential therapeutic target for smoking-related diseases.

Key Words: aging • smoking • emphysema • oxidative stress • cell migration

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Both heavy smokers and patients with Werner's syndrome manifest similar clinical features consistent with accelerated aging. Despite this, no prior studies have investigated a link between Werner's syndrome protein (WRN protein) and smoking. What This Study Adds to the Field Lung fibroblasts isolated from smokers with emphysema exhibit a decrease in WRN protein. Cigarette smoke also induces cellular senescence via WRN down-regulation in cultured fibroblasts. WRN protein may play an important role in smoking-related diseases.