Apoptosis induced by MNNG in human TK6 lymphoblastoid cells is p53 and Fas/CD95/Apo-1 related.
Agents inducing O(6)-methylguanine (O(6)MeG) in DNA, such as N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), are not only highly mutagenic and carcinogenic but also cytotoxic because of the induction of apoptosis. In CHO fibroblasts, apoptosis triggered by O(6)MeG requires cell proliferation and MutSalpha-dependent mismatch repair and is related to the induction of DNA double-strand breaks (DSBs). Furthermore, it is mediated by Bcl-2 degradation and does not require p53 for which the cells were mutated [Cancer Res. 60 (2000) 5815]. Here we studied cytotoxicity and apoptosis induced by MNNG in a pair of human lymphoblastoid cells expressing wild-type p53 (TK6) and mutant p53 (WTK1) and show that TK6 cells are more sensitive than WTK1 cells to cell killing (determined by a metabolic assay) and apoptosis. Apoptosis was a late response observed <24h after treatment and was related to accumulation of p53 and upregulation of Fas/CD95/Apo-1 receptor as well as Bax. The data indicate that MNNG induces apoptosis in lymphoblastoid cells by activating the p53-dependent Fas receptor-driven pathway. This is in contrast to CHO fibroblasts in which, in response to O(6)MeG, the mitochondrial damage pathway becomes activated.
Dunkern
Torsten
T
Division of Applied Toxicology, Institute of Toxicology, University of Mainz, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany.
Roos
Wynand
W
Kaina
Bernd
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016466:CHO Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D006224:Cricetinae; D004249:DNA Damage / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008769:Methylnitronitrosoguanidine / Q000633:toxicity*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000502:physiology*; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000187:drug effects / Q000502:physiology*
C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D008769:Methylnitronitrosoguanidine; D019950:Mitogen-Activated Protein Kinase 1