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.

Silk fibroin peptide suppresses proliferation and induces apoptosis and cell cycle arrest in human lung cancer cells

“…Changes in the activity of cyclin, CDK, and CDKI may disrupt cell proliferation, which can, in turn, lead to cancer [32]. In the present study, SFP induced an increase in the distribution of cells in the S phase, indicating cell cycle arrest of the lung cancer cell cycle in the DNA synthesis phase of the cell cycle [33]. The results revealed that SFP can influence the DNA synthesis of lung cancer cells.…”

Analysis of in situ Transcriptomes Reveals Divergent Adaptive Response to Hyper- and Hypo-Salinity in the Hong Kong Oyster, Crassostrea hongkongensis

“…Previous evidence showed that catalase can catalyze the decomposition of hydrogen peroxide, a detrimental ROS (reactive oxygen species) when produced in excess, and protect host cells against the oxidative injury in the Hong Kong oyster ( Zhang et al, 2011 ). GADD45 is another an oxidative stress response protein responsible for repairing oxidant induced DNA damage ( Li et al, 2017 ). Thus, it seems reasonable to speculate that activation of FoxO signaling and its target genes may contribute to resolution of oxidative stress under hypo-salinity.…”

The Ethanol Crude Extraction of Cyperus Rotundus Regulates Apoptosis-associated Gene Expression in HeLa Human Cervical Carcinoma Cells In Vitro

“…To investigate whether CRE induced cytotoxic effects and cell death by regulating the expression of apoptosis-associated genes in HeLa cells, we used cDNA microarray assay. CRE treatment promoted the expression of certain genes associated with DNA damage and cell growth arrest, such as DDIT3 and GADD45A (35,36). Also affected by CRE, the NCF2 gene, which encodes for the neutrophil cytosolic factor 2, is the 67-kDa cytosolic subunit of the multi-protein NADPH oxidase complex and a novel p53-targeted gene (21).…”