title: Nuclear glutathione S-transferase pi prevents apoptosis by reducing the oxidative stress-induced formation of exocyclic DNA products.
abstract: We previously found that nuclear glutathione S-transferase pi (GSTpi) accumulates in cancer cells resistant to anticancer drugs, suggesting that it has a role in the acquisition of resistance to anticancer drugs. In the present study, the effect of oxidative stress on the nuclear translocation of GSTpi and its role in the protection of DNA from damage were investigated. In human colonic cancer HCT8 cells, the hydrogen peroxide (H(2)O(2))-induced increase in nuclear condensation, the population of sub-G(1) peak, and the number of TUNEL-positive cells were observed in cells pretreated with edible mushroom lectin, an inhibitor of the nuclear transport of GSTpi. The DNA damage and the formation of lipid peroxide were dependent on the dose of H(2)O(2) and the incubation time. Immunological analysis showed that H(2)O(2) induced the nuclear accumulation of GSTpi but not of glutathione peroxidase. Formation of the 7-(2-oxo-hepyl)-substituted 1,N(2)-etheno-2'-deoxyguanosine adduct by the reaction of 13-hydroperoxyoctadecadienoic acid (13-HPODE) with 2'-deoxyguanosine was inhibited by GSTpi in the presence of glutathione. The conjugation product of 4-oxo-2-nonenal, a lipid aldehyde of 13-HPODE, with GSH in the presence of GSTpi, was identified by LS/MS. These results suggested that nuclear GSTpi prevents H(2)O(2)-induced DNA damage by scavenging the formation of lipid-peroxide-modified DNA.
authors.affiliation: Department of Neurosurgery, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 851-8523, Japan.
authors.forename: Kensaku
authors.initials: K
authors.lastname: Kamada
authors.forename: Shinji
authors.initials: S
authors.lastname: Goto
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Okunaga
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Ihara
authors.forename: Kentaro
authors.initials: K
authors.lastname: Tsuji
authors.forename: Yoshichika
authors.initials: Y
authors.lastname: Kawai
authors.forename: Koji
authors.initials: K
authors.lastname: Uchida
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Osawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsuo
authors.forename: Izumi
authors.initials: I
authors.lastname: Nagata
authors.forename: Takahito
authors.initials: T
authors.lastname: Kondo
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D003110:Colonic Neoplasms / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D005978:Glutathione / Q000494:pharmacology / Q000502:physiology; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007527:Isoenzymes / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D037102:Lectins / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D009687:Nuclear Proteins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D021381:Protein Transport / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D007527:Isoenzymes; D037102:Lectins; D009687:Nuclear Proteins; D004247:DNA; D006861:Hydrogen Peroxide; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D005978:Glutathione