title: Arsenic acid inhibits proliferation of skin fibroblasts, and increases cellular senescence through ROS mediated MST1-FOXO signaling pathway.
abstract: Arsenic exposure through drinking water is a major public health problem. It causes a number of toxic effects on skin. Arsenic has been reported to inhibit cell proliferation in in vitro conditions. However, reports about the molecular mechanisms are limited. Here, we investigated the mechanism involved in arsenic acid-mediated inhibition of cell proliferation using mouse skin fibroblast cell line. The present study found that 10 ppm arsenic acid inhibited cell proliferation, without any effect on cell death. Arsenic acid induced the generation of reactive oxygen species (ROS), resulting in oxidative stress to DNA. It also activated the mammalian Ste20-like protein kinase 1 (MST1); however the serine/threonine kinase Akt was downregulated. Forkhead box O (FOXO) transcription factors are activated through phosphorylation by MST1 under stress conditions. They are inhibited by phosphorylation by Akt through external and internal stimuli. Activation of FOXOs results in their nuclear localization, followed by an increase in transcriptional activity. Our results showed that arsenic induced the nuclear translocation of FOXO1 and FOXO3a, and altered the cell cycle, with cells accumulating at the G2/M phase. These effects caused cellular senescence. Taken together, our results indicate that arsenic acid inhibited cell proliferation through cellular senescence process regulated by MST1-FOXO signaling pathway.
authors.affiliation: Department of Applied Physiology, Faculty of Medicine, University of Miyazaki.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Harishkumar
authors.initials: H
authors.lastname: Madhyastha
authors.forename: Radha
authors.initials: R
authors.lastname: Madhyastha
authors.forename: Narantsog
authors.initials: N
authors.lastname: Choijookhuu
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hishikawa
authors.forename: Yutthana
authors.initials: Y
authors.lastname: Pengjam
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Masugi
authors.initials: M
authors.lastname: Maruyama
mesh_terms: D000818:Animals; D001149:Arsenates / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin / Q000166:cytology / Q000187:drug effects*; D000099317:Hippo Kinases
chemical_list: D001149:Arsenates; D051858:Forkhead Transcription Factors; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases; C025657:arsenic acid