Oncogenic transformation alters cisplatin-induced apoptosis in rat embryo fibroblasts

We have investigated whether cellular transformation by different oncogenes alters their responsiveness to the chemotherapeutic agent cis-diamminedichloroplatinum(II) (cDDP). Rat-6 (R6) embryo fibroblasts transformed by v-myc, rc-mos (rearranged mouse c-mos), v-src and activated c-H-ras oncogenes displayed differential sensitivities to cDDP, and the IC50 values of cDDP decreased by approximately 3.0-, 1.2-, 2.0- and 1.5-fold, respectively. Over-expression of myc, but not ras, src or mos, induced apoptosis in R6 cells. Nevertheless, all oncogenes influenced cellular susceptibility to apoptosis triggered by cDDP as judged by the appearance of condensed chromatin, formation of apoptotic bodies and internucleosomal cleavage of genomic DNA to 180 bp multimers, yielding a "laddered" electrophoretic profile on agarose gel. There was a correlation between the time- and concentration-dependent enhancement of cDDP-induced DNA fragmentation and potentiation of cDDP sensitivity by various oncogenes. Oncogenic transformation led to a decrease in expression of the PKC epsilon isoform, and stable transfection of PKC epsilon in R6 cells prevented cDDP-induced apoptosis and protected cells against cDDP cytotoxicity. Our results indicate that the differential sensitivity of oncogene-transformed cells to cDDP may be associated with the ability of various oncogenes to influence cDDP-induced apoptosis.