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Doxorubicin-induced DNA intercalation and scavenging by nuclear glutathione S-transferase pi
1Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Japan.
Abstract:
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.
Insights
Glutathione S-transferase pi (GSTpi) found in cancer cell nuclei protects DNA from anticancer drugs. Increased nuclear GSTpi enhances cancer cell resistance to chemotherapy, suggesting a new drug resistance mechanism.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Glutathione S-transferase (GST) is crucial for drug metabolism and xenobiotic detoxification.
- Increased GSTpi, a GST isozyme, is linked to cancer cell resistance against doxorubicin hydrochloride (DOX) and cis-diamminedichloroplatinum (II) (CDDP).
- Nuclear localization of GSTpi in cancer cells is observed but its functional significance remains unclear.
Purpose of the Study:
- To investigate the changes in nuclear GSTpi levels in cancer cells exposed to anticancer drugs.
- To elucidate the role of nuclear GSTpi in conferring resistance to chemotherapy.
- To explore the mechanism of nuclear transport for GSTpi.
Main Methods:
- Culturing cancer cells and treating them with anticancer drugs (DOX, CDDP).
- Quantifying nuclear GSTpi levels using biochemical assays.
- Utilizing a mushroom lectin, a nuclear transport inhibitor, to study GSTpi translocation.
Main Results:
- Nuclear GSTpi was detected in cancer cells exhibiting resistance to DOX.
- Anticancer drug treatment (DOX or CDDP) significantly increased the amount of nuclear GSTpi.
- Inhibition of nuclear transport by mushroom lectin reduced GSTpi nuclear accumulation.
- Nuclear GSTpi demonstrated a protective effect on DNA against damage induced by anticancer drugs.
Conclusions:
- The study suggests a specific transport system facilitates GSTpi's nuclear translocation.
- Nuclear GSTpi plays a role in protecting cancer cells from DNA damage caused by chemotherapy.
- These findings indicate that nuclear GSTpi may contribute to the acquisition of anticancer drug resistance in cancer cells.