title: Alterations of cellular redox state during NNK-induced malignant transformation and resistance to radiation.
abstract: Cancer cells often exhibit increased reactive oxygen species generation and altered redox regulation. The current study was conducted to investigate the biochemical and molecular events associated with redox alterations during chemical-induced malignant transformation and to evaluate their potential roles in radiation sensitivity. Immortalized nonmalignant human bronchial epithelial cells were exposed to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and a clone of cells exhibiting malignant behaviors was isolated and characterized. This clone initially exhibited an increase in cellular superoxide that eventually decreased after a long-term culture in vitro, associated with altered expression of antioxidant molecules, including an increase in thioredoxin-1 and manganese superoxide dismutase, and a decrease in glutathione peroxidase-1. These cells also showed a significant decrease in sensitivity to ionizing radiation, as demonstrated by less cell death in acute apoptosis analyses and long-term cell proliferation assays. Using biochemical redox modulation and siRNA approach, we showed that the increase in thioredoxin-1 played a significant role in conferring resistance to IR. Although there was a substantial increase in cellular glutathione, inhibition of glutathione synthesis did not increase IR sensitivity. Our study showed complex redox alterations during NNK-induced malignant transformation, and identified Trx-1 as a radiosensitivity modulator.
authors.affiliation: Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Demizu
authors.forename: Ryohei
authors.initials: R
authors.lastname: Sasaki
authors.forename: Dunyaporn
authors.initials: D
authors.lastname: Trachootham
authors.forename: Helene
authors.initials: H
authors.lastname: Pelicano
authors.forename: Justin A
authors.initials: JA
authors.lastname: Colacino
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D001980:Bronchi / Q000166:cytology; D002273:Carcinogens / Q000494:pharmacology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D009602:Nitrosamines / Q000494:pharmacology*; D010084:Oxidation-Reduction; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002273:Carcinogens; D009602:Nitrosamines; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013879:Thioredoxins; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D013482:Superoxide Dismutase; D005978:Glutathione