| Project/Area Number |
16590247
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Nagasaki University |
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Principal Investigator |
GOTO Shinji Nagasaki University, Graduate School of Biomedical Sciences, Research Associate, 大学院・医歯薬学総合研究科, 助手 (50186889)
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| Co-Investigator(Kenkyū-buntansha) |
IHARA Yoshito Nagasaki University, Graduate School of Biomedical Sciences, Associate Professor, 大学院・医歯薬学総合研究科, 助教授 (70263241)
KONDO Takahito Nagasaki University, Graduate School of Biomedical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (00158908)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | glutathione S-transferase π / oxidative stress / exocyclic DNA adducts / anti-cancer drug resistance / nucleus / nuclear localization signal / mitochondria import signal / mitochondria |
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| Research Abstract |
We previously found that nuclear glutathione S-transferase π(GSTπ) 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 GSTπ and its role in the protection of DNA from damage were investigated. In human colonic cancer HCT8 cells, the hydrogen peroxide (H_2O_2)-induced increase in nuclear condensation, the population of sub-G, peak, and the number of TUNEL-positive cells were observed in cells pretreated with edible mushroom lectin, an inhibitor of the nuclear transport of GSTπ. The DNA damage and the formation of lipid peroxide were dependent on the dose of H_2O_2 and the incubation time. Immunological analysis showed that H_2O_2 induced the nuclear accumulation of GSTπ 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-hydro
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peroxyoctadecadienoic acid (13-HPODE) with 2'-deoxyguanosine was inhibited by GSTπ 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 GSTπ, was identified by LS/MS. These results suggested that nuclear GSTπ prevents H_2O_2-induced DNA damage by scavenging the formation of lipid-peroxide-modified DNA.
Moreover, we evaluated the clinical significance of nuclear GSTπ in gynaecological cancer. We carried out an immunohistochemical analysis of GSTπ, and examined the correlation between nuclear GSTπ expression and prognosis in 43 epithelial ovarian cancers. We compared expression levels before and after chemotherapy in uterine cervical cancers and endometrial cancers. The 5-year progression-free survival rate of the nuclear GSTπ-positive group was lower than that of the cytoplasmic GSTπ-positive group, and was significantly lower than that of the negative group. The expression of nuclear GSTπ was compared before and after chemotherapy in uterine cervical and endometrial cancers. In eight out of 12 cases, the expression turned positive after the chemotherapy. We suggest that nuclear localisation of GSTπ is associated with drug resistance. The nuclear localisation of GSTπ in tumour cells is a useful prognosticator, and may contribute to the selection of anticancer drugs for gynaecological cancers. Less
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