title: The inhibition of HIF-2α on the ATM/Chk-2 pathway is involved in the promotion effect of arsenite on benzo(a)pyrene-induced cell transformation.
abstract: Both arsenite and benzo(a)pyrene (BaP) are known human carcinogens. Studies on the mode-of-action of arsenite indicate that it can also act as co-carcinogen or as a cancer promoter, and that it can facilitate progression of cancers. Some studies on development of lung cancers have suggested a synergism between arsenite exposure and cigarette smoking. The mechanism of action for such an effect, however, remains obscure. In the present study, we investigated the effects of HIF-2α on arsenite- and BaP-induced cell malignant transformation as well as on signal transduction pathways in human bronchial epithelial (HBE) cells. The results show that arsenite accelerates the neoplastic transformation and migration of cells and enhances chromosomal aberrations induced by BaP. HIF-2α is involved in blocking the effects of arsenite in activating the ATM/Chk-2 pathway and in repair of DNA damage induced by BaP. Moreover, blocking of HIF-2α prevents the effects of arsenite on the neoplastic transformation, cell migration, and chromosomal aberrations caused by BaP. These results indicate that the repressive effect of HIF-2α on the ATM/Chk-2 pathway leads to genomic instability, which is involved in arsenite-accelerated, BaP-induced malignant transformation of HBE cells.
authors: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China.
authors: Ying
authors: Y
authors: Pang
authors: Yuan
authors: Y
authors: Xu
authors: Huiqiao
authors: H
authors: Li
authors: Yuan
authors: Y
authors: Li
authors: Yue
authors: Y
authors: Zhao
authors: Rongrong
authors: R
authors: Jiang
authors: Lu
authors: L
authors: Shen
authors: Jianwei
authors: J
authors: Zhou
authors: Xinru
authors: X
authors: Wang
authors: Qizhan
authors: Q
authors: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D018053:Arsenites / Q000378:metabolism / Q000633:toxicity*; D064007:Ataxia Telangiectasia Mutated Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity*; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced; D064447:Checkpoint Kinase 2; D002869:Chromosome Aberrations; D020552:Comet Assay; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D018053:Arsenites; D064007:Ataxia Telangiectasia Mutated Proteins; D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene; D018797:Cell Cycle Proteins; D064447:Checkpoint Kinase 2; D004268:DNA-Binding Proteins; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C576324:ATM protein, human; C578634:CHEK2 protein, human; C015001:arsenite