H. Seimiya et al., C-JUN NH2-TERMINAL KINASE-MEDIATED ACTIVATION OF INTERLEUKIN-1-BETA CONVERTING ENZYME CED-3-LIKE PROTEASE DURING ANTICANCER DRUG-INDUCED APOPTOSIS/, The Journal of biological chemistry, 272(7), 1997, pp. 4631-4636
Upon treatment with various anticancer drugs, myeloid leukemia U937 ce
lls undergo apoptosis. In this study, we found that either etoposide (
VP-16) or camptothecin (CPT) activated c-Jun N-terminal kinase 1/stres
s-activated protein kinase (JNK1/SAPK), transient c-jun expression, an
d ICE (interleukin-1 beta converting enzyme)/CED-3-like proteases in U
937 cells. Phorbol ester-resistant U937 variant, UT16 cells, displayed
a decreased susceptibility to apoptosis induced by these drugs. The d
rugs did not cause JNK1 activation, c-jun expression, nor activation o
f ICE/CED-3-like proteases in UT16 cells. As reported previously, benz
yloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene (Z-Asp), a preferential
inhibitor of ICE/CED-3-like proteases, blocked the apoptosis of U937
cells. Interestingly, however, Z-Asp did not inhibit JNK1 activation i
n either VP-16- or CPT-treated U937 cells. The JNK1 antisense oligonuc
leotides diminished protein expression of JNK1 and inhibited drug-indu
ced apoptosis of U937 cells, whereas sense control oligonucleotides di
d not. Consistent with this observation, the antisense oligonucleotide
-treated cells did not respond to VP-16 or CPT with Z-Asp-sensitive pr
oteases. These results indicate that JNK1 triggers the DNA damaging dr
ug-induced apoptosis of U937 cells by activating Z-Asp-sensitive ICE/C
ED-3-like proteases.