DNA repair profile in gastrointestinal stromal tumors (gists) - novel perspectives for therapy

Aim. To assess the expression of various types of DNA repair proteins in gastrointestinal stromal tumors (GISTs) to identify the possible defects in DNA repair pathways and therapeutic targets. Methods. The study was performed on the human fibroblasts, imatinib-sensitive vs imatinib-resistant GISTs and leiomyosarcomas (LMS) cell lines, as well. The cell lines indicated above were cultured in the corresponding culture medium supplemented with fetal bovine serum, L-glutamine and antibiotics (37 °C и 5% СО2). Protein expression level and its intracellular localization were assessed by Western blotting. Results. The reduced BRCA1 expression was observed in most of the GIST cell lines, which was associated with an up-regulation of Rad51, thereby indicating about the potential abnormalities of homologous recombination pathway in these cells. This phenomenon was typical for GISTs and was not observed in LMS cells lines. In contrast to LMS cell lines, all GIST cells showed an upregulation of O6-methylguanine DNA methyltransferase (MGMT), the key enzyme involved in alkylated DNA damage repair pathway. Most GIST cells exhibited high level of MSH6 known as a key member of mismatch repair pathway. Most notably, topoisomerases were over-expressed in all of GIST cell lines. Conclusions. We found several striking alterations in expression levels of DDR pathway enzymes in GISTs. For instance, an up-regulation of topoisomerases in all GISTs indicates that these cells might be sensitive to topoisomerase II inhibitors and could be potentially targeted therapeutically.

GIST, DNA damage repair, chemotherapy