Treatment > Chemoresistance

Meeting Abstract

Transcriptional activitation of the GSTP1 gene by wind-type p53 results in a DNA-mismatch-repair–dependent NER: a novel p53-GSTP1 mediated mechanism of alkylator resistance in human gliomas

Francis Ali-Osman, Olanike Akande, Gamil Antoun, and Henry Friedman

Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA, and Duke University, Durham, North Carolina, USA

The contribution of the tumor suppressor gene, p53, to treatment outcome in gliomas has been controversial, with different results reported for pediatric and adult gliomas. 
We report here that the human GSTP1 gene, whose overexpression and nuclear localization is associated with drug resistance and poor survival in human glioma patients, is transcriptionally activated by wild-type (wt) p53, but not mutant p53, via binding to a novel p53 consensus motif in intron 4 of the GSTP1 gene. 
cDNA array and Northern analyses showed the p53-dependent increase in GSTP1 expression to be associated with increased transcripts of the DNA mismatch repair (MMR) gene hMLH1 in human glioblastoma cells. 
GSTP1-deficient glioma cells genetically engineered to be GSTP1 positive also showed increased hMLH1 gene transcripts. 
Because MMR has been linked to transcription-coupled nucleotide excision repair (TC-NER), a major mechanism of tumor resistance to several clinically active antiglioma agents, we measured the level of TC-NER in the cells following exposure to cisplatin. 
The results showed a 4-fold increase in NER in the GSTP1-positive glioma cells compared with their isogenic GSTP1-negative counterpart. 
This was accompanied by a 3.4-fold increase in cisplatin resistance of the former over the latter. 
Preliminary results with primary glioblastomas from 11 patients indicate a correlation between GSTP1 expression, cisplatin resistance, and absence of p53 mutations (exons 4–8). 
These observations indicate a novel mechanism of GSTP1-mediated drug resistance resulting from the cross talk between p53 and the GSTP1 gene in human gliomas. 
The results also shed light on the conflicting results of the role of p53 in tumor drug resistance and indicate that this may result, at least in part, from a complex interplay between the level of GSTP1 expression, the MMR functional status, and the mutational state of the p53 gene in the tumors. 
The data also provide additional evidence supporting a link between MMR and TC-NER in human gliomas. 

(Supported by NIH Grants RO1 CA79644, CA91438 and T32 CA73954 to FAO).

Copyright © 2003 by the Society for Neuro-Oncology