Nuclear glutathione S-transferase pi prevents apoptosis by reducing the oxidative stress-induced formation of exocyclic DNA products.
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.
Kamada
Kensaku
K
Department of Neurosurgery, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 851-8523, Japan.
Goto
Shinji
S
Okunaga
Tomohiro
T
Ihara
Yoshito
Y
Tsuji
Kentaro
K
Kawai
Yoshichika
Y
Uchida
Koji
K
Osawa
Toshihiko
T
Matsuo
Takayuki
T
Nagata
Izumi
I
Kondo
Takahito
T
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
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