Involvement of apoptosis in mitomycin C hypersensitivity of Chinese hamster cell mutants

To elucidate the mechanisms of the mammalian cell defense against cross-lin king agents, we studied previously cellular responses to mitomycin C (MMC) treatment in two MMC-hypersensitive hamster cell mutants' V-H4 and V-C8, as well as their parental cell line V79. In the present report, we investigat ed whether alterations in cell cycle checkpoints and induction of apoptosis could be responsible for the MMC hypersensitivity of the V-H4 and V-C8 mut ant cell lines. First, we found that parental and mutant cells exhibited si milar cell cycle responses to MMC concentrations of equivalent cytotoxicity , arguing against a defective cell cycle checkpoint in hypersensitive cell lines. In contrast, we showed that mutant cells underwent greater levels of apoptosis following MMC treatment than parental cells. These findings indi cate that increased induction of apoptosis contributes to the hypersensitiv ity of V-H4 and V-C8 cells to the growth inhibitory effect of MMC. This dif ferential apoptotic response was observed with both equimolar and equitoxic MMC doses and was specific to the cross-linking agent MMC, suggesting that control of the apoptotic process is altered in both MMC-hypersensitive mut ants. The defective genes in V-H4 and V-C8 cells would then function in the regulation of an apoptotic pathway triggered by MMC-induced damage and ind ependent of p53-mediated transcription. (C) 2000 Elsevier Science Inc.