gms | German Medical Science

Objective: The glutathione S-transferase pi gene (GSTP1) is a polymorphic gene encoding active, functionally different GSTP1 variant proteins that are thought to function in xenobiotic metabolism and which may play a role in susceptibility to cancer, and other diseases. Our hypothesis was that there is a relation of this protein to the grade of malignancy and chemoresistance in glioma. Therefore, we set out to measure the GSTP1 expression at the mRNA and protein level in order to elucidate the potential role of GSTP1 expression as a biomarker for disease progression and predictor of chemotherapeutic effect.

Method: We quantified the expression of the drug-metabolizing gene GSTP1 using real-time RT-PCR. 70 astrocytic tumor samples were used including all three degrees of malignancy (grade II-IV), primary and recurrent gliomas, pure and mixed astrocytic tumors, with and without chemotherapy (CTx; n=10 per group). Moreover, we did a longitudinal analysis of tumor recurrence and disease progression in individual patients. In addition, protein expression and localization was evaluated by Western Blotting and immunohistochemistry in order to validate the PCR findings by comparing GSTP1 expression in five different groups: diffuse-, anaplastic astrocytomas, glioblastomas (GBM) – before and after CTx – as well as peritumoral control tissue.

Results: There were no changes in GSTP1 mRNA expression, determined by quantitative RT-PCR, between diffuse astrocytomas (1.80±0.85), anaplastic astrocytomas (2.53±2.13), secondary GBM without- (2.48±1.02) and with chemotherapy (2.57±1.40), primary GBM (1.95±1.14) and recurrent primary GBM after Stupp protocol (3.13±1.70). The latter difference could indicate a trend towards an upregulation of GSTP1 after radiochemotherapy in primary GBM (p=0.08). In contrast, no difference at all was seen between secondary GBM before and after radio-/chemotherapy. The variance within all groups was very high. Western blotting revealed similar results. Immunohistochemistry revealed high GSTP1 expression throughout the all tissues.

Conclusions: The expression of GSTP was highly heterogeneous within the surgical specimens. No significant differences in gene expression were detected between primary or recurrent gliomas, suggesting that glioma chemoresistance is mostly intrinsic. However, while GSTP1 is the primary isoenzyme contributing to total GST activity in both, normal brain and brain tumors, the endogenous neuronal expression level can be too high to distinguish the GSTP alteration in tumor cells