Polychlorinated Biphenyl Quinone Metabolite Promotes p53-Dependent DNA Damage Checkpoint Activation, S-Phase Cycle Arrest and Extrinsic Apoptosis in Human Liver Hepatocellular Carcinoma HepG2 Cells

Xiufang Song; Lingrui Li; Qiong Shi; Hans-Joachim Lehmler; Juanli Fu; Chuanyang Su; Xiaomin Xia; Erqun Song; Yang Song

doi:10.1021/acs.chemrestox.5b00320

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Polychlorinated Biphenyl Quinone Metabolite Promotes p53-Dependent DNA Damage Checkpoint Activation, S-Phase Cycle Arrest and Extrinsic Apoptosis in Human Liver Hepatocellular Carcinoma HepG2 Cells

Journal article

Peer reviewed

Polychlorinated Biphenyl Quinone Metabolite Promotes p53-Dependent DNA Damage Checkpoint Activation, S-Phase Cycle Arrest and Extrinsic Apoptosis in Human Liver Hepatocellular Carcinoma HepG2 Cells

Xiufang Song, Lingrui Li, Qiong Shi, Hans-Joachim Lehmler, Juanli Fu, Chuanyang Su, Xiaomin Xia, Erqun Song and Yang Song

Chemical research in toxicology, Vol.28(11), pp.2160-2169

11/16/2015

DOI: 10.1021/acs.chemrestox.5b00320

PMID: 26451628

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Abstract

Polychlorinated biphenyls (PCBs) are a group of persistent organic pollutants. The toxic behavior and mechanism of PCBs individuals and congeners have been extensively investigated. However, there is only limited information on their metabolites. Our previous studies have shown that a synthetic PCB metabolite, PCB29-pQ, causes oxidative damage with the evidence of cytotoxicity, genotoxicity, and mitochondrial-derived intrinsic apoptosis. Here, we investigate the effects of PCB29-pQ on DNA damage checkpoint activation, cell cycle arrest, and death receptor-related extrinsic apoptosis in human liver hepatocellular carcinoma HepG2 cells. Our results illustrate that PCB29-pQ increases the S-phase cell population by down-regulating cyclins A/D1/E, cyclin-dependent kinases (CDK 2/4/6), and cell division cycle 25A (CDC25A) and up-regulating p21/p27 protein expressions. PCB29-pQ also induces apoptosis via the up-regulation of Fas/FasL and the activation of caspase 8/3. Moreover, p53 plays a pivotal role in PCB29-pQ-induced cell cycle arrest and apoptosis via the activation of ATM/Chk2 and ATR/Chk1 checkpoints. Cell cycle arrest and apoptotic cell death were attenuated by the pretreatment with antioxidant N-acetyl-cysteine (NAC). Taken together, these results demonstrate that PCB29-pQ induces oxidative stress and promotes p53-dependent DNA damage checkpoint activation, S-phase cycle arrest, and extrinsic apoptosis in HepG2 cells.

Protein Kinases - metabolism

Cell Survival - drug effects

Apoptosis - drug effects

Humans

Cell Cycle Proteins - metabolism

Tumor Suppressor Protein p53 - metabolism

Hep G2 Cells

Checkpoint Kinase 2 - metabolism

Polychlorinated Biphenyls - toxicity

Cell Cycle Checkpoints - drug effects

Liver Neoplasms - metabolism

Benzoquinones - toxicity

Checkpoint Kinase 1

DNA Damage

Carcinoma, Hepatocellular - metabolism

Details

Title: Subtitle: Polychlorinated Biphenyl Quinone Metabolite Promotes p53-Dependent DNA Damage Checkpoint Activation, S-Phase Cycle Arrest and Extrinsic Apoptosis in Human Liver Hepatocellular Carcinoma HepG2 Cells
Creators: Xiufang Song - Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, People's Republic of China
Lingrui Li - Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, People's Republic of China
Qiong Shi - Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, People's Republic of China
Hans-Joachim Lehmler - Department of Occupational and Environmental Health, College of Public Health, The University of Iowa , Iowa City, Iowa 52242, United States
Juanli Fu - Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, People's Republic of China
Chuanyang Su - Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, People's Republic of China
Xiaomin Xia - Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, People's Republic of China
Erqun Song - Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, People's Republic of China
Yang Song - Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University , Chongqing 400715, People's Republic of China
Resource Type: Journal article
Publication Details: Chemical research in toxicology, Vol.28(11), pp.2160-2169
DOI: 10.1021/acs.chemrestox.5b00320
PMID: 26451628
NLM abbreviation: Chem Res Toxicol
ISSN: 0893-228X
eISSN: 1520-5010
Publisher: United States
Grant note: P30 ES005605 / NIEHS NIH HHS
Language: English
Date published: 11/16/2015
Academic Unit: Occupational and Environmental Health; Iowa Neuroscience Institute
Record Identifier: 9984001089402771

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