Induction of JNK and c-Abl signalling by cisplatin and oxaliplatin in mismatch repair-proficient and -deficient cells

Loss of DNA mismatch repair has been observed in a variety of human cancers . Recent studies have shown that loss of DNA mismatch repair results in res istance to cisplatin but not oxaliplatin, suggesting that the mismatch repa ir proteins serve as a detector for cisplatin but not oxaliplatin adducts. To identify the signal transduction pathways with which the detector commun icates, we investigated the effect of loss of DNA mismatch repair on activa tion of known damage-responsive pathways, and recently reported that cispla tin differentially activates c-Jun NH2-terminal kinase (JNK) and c-Abl in r epair-proficient vs.-deficient cells. In the current study, we directly com pared differential activation of these pathways by cisplatin vs, oxaliplati n. The results confirm that cisplatin activates JNK kinase 5.7 +/- 1.5 (s.d .)-fold more efficiently in DNA mismatch repair-proficient than repair-defi cient cells, and that the c-Abl response to cisplatin is completely absent in DNA mismatch repair-deficient cells. In contrast, there was no detectabl e activation of the JNK or c-Abl kinases in DNA mismatch repair-proficient or -deficient cells exposed to oxaliplatin. The present study demonstrates that, despite the similarity of the adducts produced by cisplatin and oxali platin, they appear to be recognized by different detectors. The DNA mismat ch repair system plays an important part in the recognition of cisplatin ad ducts, and activation of both the JNK and c-Abl kinases in response to cisp latin damage is dependent on the detector function of the DNA mismatch repa ir proteins. in contrast, this detector does not respond to oxaliplatin add ucts.