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Glutathione S-transferase activity and subunit composition in transitional cell cancer and mucosa of the human
C L Berendsen1, W H Peters, P G Scheffer
1Department of Urology, Free University Hospital, Amsterdam, The Netherlands.
Objectives:
Clinical data indicate that drug resistance to chemotherapy may occur in all stages of transitional cell cancer (TCC). Glutathione S-transferases (GSTs) are a family of detoxification enzymes composed of four different classes, denoted alpha (GSTA), mu (GSTM), pi (GSTP), and theta (GSTT), each containing one or more homo- or heterodimeric isoforms (GSTA1-1, GSTA1-2, and so forth), GSTs play a prominent role in drug detoxification and have been associated with resistance of tumor cells to anticancer agents. GST activity and isoenzyme levels were studied in TCC and normal bladder mucosa.
Methods:
Enzyme activity was studied in samples of TCC (n = 37), adjacent normal bladder mucosa (n = 37), and in bladder mucosa of control patients without TCC (n = 46). GST isoenzyme composition was studied in mucosa and TCC of 14 patients and 11 controls.
Results:
The mucosa of patients with TCC showed GST activity (191 +/- 21 nmol/min/mg cytosolic protein), similar to the mucosa of controls (176 +/- 15 nmol/min/mg). GST activity was significantly increased in TCC (666 +/- 157 nmol/min/mg) in comparison with adjacent mucosa (P < 0.003). In mucosa samples, the levels of GSTA (A1-1, A1-2, and A2-2) were below the detection limit in 92% of the samples. GSTM (GSTM1-1) was found in 9 controls and in 7 patients with TCC but not in the other 7 patients, whereas GSTP (GSTP1-1) could be detected in all samples. The levels of GSTM1-1 and GSTP1-1 were similar in mucosa of patients and controls. The mean relative increase of GSTP1-1 levels in TCC was 4.6-fold (P < 0.002). In the 7 patients with GSTM1-1-detectable expression in adjacent normal mucosa, mean GSTM1-1 levels in TCC were increased 2.8-fold compared with mean levels in normal adjacent mucosa (P < 0.02). GSTA was measured in five samples of TCC at relatively low levels.
Conclusions:
Overexpression of GSTP1-1 and GSTM1-1 may suggest that in the process of TCC carcinogenesis, a selection pressure occurs, resulting in a tumor with enhanced detoxification properties, including that of therapeutic drugs.
Insights
Glutathione S-transferases (GSTs) are elevated in transitional cell cancer (TCC), suggesting tumors develop enhanced drug detoxification. This may explain chemotherapy resistance in TCC patients.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Drug resistance is a significant challenge in treating transitional cell cancer (TCC).
- Glutathione S-transferases (GSTs) are key detoxification enzymes implicated in tumor resistance to anticancer agents.
- GSTs comprise four classes (GSTA, GSTM, GSTP, GSTT) with various isoforms.
Purpose of the Study:
- To investigate GST activity and isoenzyme levels in TCC and normal bladder mucosa.
- To understand the role of GSTs in TCC drug resistance.
Main Methods:
- Enzyme activity assays were performed on TCC samples (n=37), adjacent normal mucosa (n=37), and control mucosa (n=46).
- GST isoenzyme composition was analyzed in 14 TCC patients and 11 controls.
- Levels of GSTA, GSTM (GSTM1-1), and GSTP (GSTP1-1) were quantified.
Main Results:
- GST activity was significantly higher in TCC (666 +/- 157 nmol/min/mg) compared to adjacent mucosa (191 +/- 21 nmol/min/mg).
- GSTP1-1 was detected in all samples, with a 4.6-fold increase in TCC.
- GSTM1-1 showed a 2.8-fold increase in TCC compared to normal mucosa in patients where it was detectable.
Conclusions:
- Overexpression of GSTP1-1 and GSTM1-1 in TCC suggests a tumor selection process.
- This selection favors enhanced detoxification properties, potentially including therapeutic drugs.
- Elevated GST levels may contribute to chemotherapy resistance in transitional cell cancer.