INCREASED C-JUN AP-1 LEVELS IN ETOPOSIDE-RESISTANT HUMAN LEUKEMIA K562 CELLS/

C-jun mRNA and AP-1 levels were examined in etoposide (VP-16)-sensitiv e (K562) and -resistant (K/VP.5) human leukemia cell lines. Previously , we reported that K/VP.5 cells have increased basal levels of mRNA fo r the protooncogene c-jun (Ritke MK and Yalowich JC, Biochem Pharmacol 46: 2007-2020, 1993). In this study, we show that the 3-fold increase in c-jun transcripts in K/VP.5 cells was accompanied by a 2-fold incr ease in the stability of the mRNA for this gene and a nearly 2-fold in crease in AP-1 DNA binding activity compared with parental K562 cells. Treatment of K562 and K/VP.5 cells with 50-200 mu M VP-16 resulted in 3- to 10-fold stimulation of c-jun transcripts, which peaked 90-150 m in after addition of drug and remained elevated up to 5 hr. In contras t, amsacrine stimulated the levels of c-jun mRNA only 3-fold in both c ell lines, and its c-jun stimulatory effects were decreased at concent rations greater than 50 mu M. VP-16 stimulation of c-jun mRNA levels r esulted in a 2-fold increase in AP-1 binding activity in K562 but not in K/VP.5 cells. Taken together, these results suggest that posttransc riptional changes in c-jun mRNA regulation may be associated with acqu ired resistance to VP-16.