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Molecules 2017, 22(1), 124; doi:10.3390/molecules22010124

GADD45a Regulates Olaquindox-Induced DNA Damage and S-Phase Arrest in Human Hepatoma G2 Cells via JNK/p38 Pathways

College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No.2, Haidian District, Beijing 100193, China
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Academic Editors: Luciano Saso, László Dux, Grzegorz Wegrzyn and Tamás Csont
Received: 15 November 2016 / Revised: 28 December 2016 / Accepted: 9 January 2017 / Published: 13 January 2017
(This article belongs to the Special Issue Chemistry and Pharmacology of Modulators of Oxidative Stress)
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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. View Full-Text
Keywords: olaquindox; GADD45a; DNA damage; S-phase arrest; JNK/p38 pathways olaquindox; GADD45a; DNA damage; S-phase arrest; JNK/p38 pathways
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Li, D.; Dai, C.; Yang, X.; Li, B.; Xiao, X.; Tang, S. GADD45a Regulates Olaquindox-Induced DNA Damage and S-Phase Arrest in Human Hepatoma G2 Cells via JNK/p38 Pathways. Molecules 2017, 22, 124.

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