Increased c- jun/AP-1 levels in etoposide-resistant human leukemia K562 cells

Abstract

C- jun mRNA and AP-1 levels were examined in etoposide (VP-16)-sensitive (K562) and -resistant (K/VP.5) human leukemia cell lines. Previously, we reported that K/VP.5 cells have increased basal levels of mRNA for 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 increase in the stability of the mRNA for this gene and a nearly 2-fold increase in AP-1 DNA binding activity compared with parental K562 cells. Treatment of K562 and K/VP.5 cells with 50–200 μM VP-16 resulted in 3- to 10-fold stimulation of c- jun transcripts, which peaked 90–150 min after addition of drug and remained elevated up to 5hr. In contrast, amsacrine stimulated the levels of c- jun mRNA only 3-fold in both cell lines, and its c- jun stimulatory effects were decreased at concentrations greater than 50 μM. VP-16 stimulation of c- jun mRNA levels resulted 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 posttranscriptional changes in c- jun mRNA regulation may be associated with acquired resistance to VP-16.