title: Investigation of cell death induced by N-methyl-N-nitrosourea in cell lines of human origin and implication of RNA binding protein alterations.
abstract: Methylating agents, a widely used class of anticancer drugs, induce DNA methylation adducts, the most biologically significant being O(6)-methylguanine. The efficacy of these drugs depends on the interplay of three DNA repair systems: base excision repair (BER), methyl-directed mismatch repair (MMR) and direct damage reversal by O(6)-methylguanine-DNA methyltransferase (MGMT). An MGMT-inducible, MMR- and BER-proficient HeLa cell line was treated with different concentrations of N-methyl-N-nitrosourea (MNU), a model S(N)1 methylating agent, analogous to widely used methylating cancer chemotherapeutic drugs, under different expression levels of the repair enzyme (MGMT). MNU induced MGMT-dependent apoptotic cell death. In this particular cellular context, the induction of apoptosis was accompanied by modifications of the RNA binding protein poly(A)polymerase and significant down-regulation of the heterogeneous nuclear ribonucleoprotein (hnRNP) C1/C2. These results implicate alterations of the above mentioned RNA binding proteins in S(N)1 methylating agent-induced cell death and apoptosis, providing a possible perspective regarding their use as biomarkers of tumor resistance/sensitivity to chemotherapy.
authors.affiliation: Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
authors.forename: A
authors.initials: A
authors.lastname: Koryllou
authors.forename: M
authors.initials: M
authors.lastname: Patrinou-Georgoula
authors.forename: A
authors.initials: A
authors.lastname: Dimozi
authors.forename: S A
authors.initials: SA
authors.lastname: Kyrtopoulos
authors.forename: V
authors.initials: V
authors.lastname: Pletsa
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D053843:DNA Mismatch Repair; D004260:DNA Repair; D006367:HeLa Cells; D006801:Humans; D008770:Methylnitrosourea / Q000494:pharmacology*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D020033:Protein Isoforms; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D008770:Methylnitrosourea; D019853:O(6)-Methylguanine-DNA Methyltransferase