Doxorubicin-induced DNA intercalation and scavenging by nuclear glutathione S-transferase pi.
Glutathione S-transferase (GST) functions in xenobiotic biotransformation and drug metabolism. Increased expression of GSTpi, an isozyme of GST, has been found in cancer cells resistant to doxorubicin hydrochloride (DOX) or cis-diamminedichloroplatinum (II) (CDDP), and this increase was believed to be correlated with drug resistance of cancer cells. GST is mainly expressed in the cytoplasm; GSTpi in the nucleus has been reported in cancer cells, but the meaning of this result is not known. Here, we studied changes in the amount of nuclear GSTpi after exposure of cancer cells to anticancer drugs, and role of the nuclear GSTpi in drug resistance. We found nuclear GSTpi in cancer cells resistant to DOX, and the amount of nuclear GSTpi was enhanced by treatment of the cancer cells with DOX or CDDP. We also found that a mushroom lectin, an inhibitor of nuclear transport, inhibited the nuclear transfer of GSTpi, suggesting the existence of a specific transport system for the nuclear transfer of GSTpi. Nuclear GSTpi protected DNA against damage by anticancer drugs. These results suggest a possible role of GSTpi in the acquisition of resistance to anticancer drugs by cancer cells.
Goto
S
S
Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Japan.
Ihara
Y
Y
Urata
Y
Y
Izumi
S
S
Abe
K
K
Koji
T
T
Kondo
T
T
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002467:Cell Nucleus / Q000201:enzymology* / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects / Q000201:enzymology; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D000077146:Irinotecan; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism*; D037102:Lectins / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
C041433:Agaricus lectins; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007527:Isoenzymes; D037102:Lectins; D000077146:Irinotecan; D004317:Doxorubicin; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D002945:Cisplatin; D002166:Camptothecin