The inhibition of ERK/MAPK not the activation of JNK/SAPK is primarily required to induce apoptosis in chronic myelogenous leukemic K562 cells

in this study, the downstream signaling of Bcr-Abl tyrosine kinase responsi ble for apoptosis resistance was investigated. DNA fragmentation, a hallmar k of apoptosis, was observed after 2 days of herbimycin A treatment with a peak on 3 day. During the apoptosis induced by the treatment of herbimycin A, stress-activated protein kinase (SAPK) and p38 kinase were activated tim e- and dose-dependently, while extracellular signal-regulated kinase (ERK) was inhibited. However, apoptosis was induced by the treatment of PD98059, a specific inhibitor of MEK (MAPK or ERK kinase), not by the treatment of s orbitol, a strong activator of SAPK and p38 kinase. Although K562 cells wer e very resistant to sorbitol-induced apoptosis, DNA fragmentation was induc ed rapidly in Jurkat, HL-60 and U937 cells after exposure to sorbitol, desp ite that these apoptosis-sensitive cells have similar or lower activities o f JNK/SAPK and p38 kinase compared with K562 cells after treatment of sorbi tol. K562 cells had a much higher basal activity of ERK/MAPK than other apo ptosis-sensitive cell lines, which were very susceptible to apoptosis induc ed by low dose of PD98059 compared with K562 cells. In HL-60 cells, sorbito l-induced apoptosis was prevented by the treatment of phorbol myristate 13- acetate (PMA), which activates the ERK/MAPK pathway, and this was blocked b y PD98059. From these results, it could be suggested that the inhibition of ERK/MAPK not the activation of JNK/SAPK is primarily required to induce ap optosis in K562 cells. (C) 2000 Published by Elsevier Science Ltd. All righ ts reserved.