title: 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.
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.
authors.affiliation: 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.
authors.forename: Xiufang
authors.initials: X
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Lingrui
authors.initials: L
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Occupational and Environmental Health, College of Public Health, The University of Iowa , Iowa City, Iowa 52242, United States.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Lehmler
authors.affiliation: 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.
authors.forename: Juanli
authors.initials: J
authors.lastname: Fu
authors.affiliation: 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.
authors.forename: Chuanyang
authors.initials: C
authors.lastname: Su
authors.affiliation: 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.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Xia
authors.affiliation: 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.
authors.forename: Erqun
authors.initials: E
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D004249:DNA Damage; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011494:Protein Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C587734:2,3,5-trichloro-6-phenyl-(1,4)benzoquinone; D016227:Benzoquinones; D018797:Cell Cycle Proteins; D016159:Tumor Suppressor Protein p53; D011078:Polychlorinated Biphenyls; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1