title: GADD45a Regulates Olaquindox-Induced DNA Damage and S-Phase Arrest in Human Hepatoma G2 Cells via JNK/p38 Pathways.
abstract: Olaquindox, a quinoxaline 1,4-dioxide derivative, is widely used as a feed additive in many countries. The potential genotoxicity of olaquindox, hence, is of concern. However, the proper mechanism of toxicity was unclear. The aim of the present study was to investigate the effect of growth arrest and DNA damage 45 alpha (GADD45a) on olaquindox-induced DNA damage and cell cycle arrest in HepG2 cells. The results showed that olaquindox could induce reactive oxygen species (ROS)-mediated DNA damage and S-phase arrest, where increases of GADD45a, cyclin A, Cdk 2, p21 and p53 protein expression, decrease of cyclin D1 and the activation of phosphorylation-c-Jun N-terminal kinases (p-JNK), phosphorylation-p38 (p-p38) and phosphorylation-extracellular signal-regulated kinases (p-ERK) were involved. However, GADD45a knockdown cells treated with olaquindox could significantly decrease cell viability, exacerbate DNA damage and increase S-phase arrest, associated with the marked activation of p-JNK, p-p38, but not p-ERK. Furthermore, SP600125 and SB203580 aggravated olaquindox-induced DNA damage and S-phase arrest, suppressed the expression of GADD45a. Taken together, these findings revealed that GADD45a played a protective role in olaquindox treatment and JNK/p38 pathways may partly contribute to GADD45a regulated olaquindox-induced DNA damage and S-phase arrest. Our findings increase the understanding on the molecular mechanisms of olaquindox.
authors.affiliation: College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No.2, Haidian District, Beijing 100193, China. lidaowen123.fff@163.com.
authors.forename: Daowen
authors.initials: D
authors.lastname: Li
authors.affiliation: College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No.2, Haidian District, Beijing 100193, China. daichongshan@cau.edu.cn.
authors.forename: Chongshan
authors.initials: C
authors.lastname: Dai
authors.affiliation: College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No.2, Haidian District, Beijing 100193, China. fujianlw@163.com.
authors.forename: Xiayun
authors.initials: X
authors.lastname: Yang
authors.affiliation: College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No.2, Haidian District, Beijing 100193, China. lb2016@cau.edu.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No.2, Haidian District, Beijing 100193, China. xiaoxilong1958@163.com.
authors.forename: Xilong
authors.initials: X
authors.lastname: Xiao
authors.affiliation: College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No.2, Haidian District, Beijing 100193, China. tssfj@cau.edu.cn.
authors.forename: Shusheng
authors.initials: S
authors.lastname: Tang
mesh_terms: D000821:Animal Feed / Q000032:analysis; D000873:Anthracenes / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D053938:DNA Fragmentation / Q000187:drug effects; D005503:Food Additives / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D000873:Anthracenes; D000900:Anti-Bacterial Agents; D018797:Cell Cycle Proteins; D005503:Food Additives; D007093:Imidazoles; D048670:MAP Kinase Kinase 4; D009687:Nuclear Proteins; D011725:Pyridines; D011810:Quinoxalines; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C432165:pyrazolanthrone; C013168:olaquindox; C093642:SB 203580
keywords: DNA damage; GADD45a; JNK/p38 pathways; S-phase arrest; olaquindox