Activation of PKC but not of ERK is required for vitamin E-succinate-induced apoptosis of HL-60 cells

Vitamin E-succinate (VES) induced HL-60 human leukemia cells to undergo apo ptosis. Treatment with VES induced membrane translocation of Fas; cleavages of caspase-3, PARP, and lamin B; hypophosphorylation of retinoblastoma pro tein; and increase of p21(WAF1) protein level. During the induction of apop tosis, activity of PKC was gradually increased with downregulation of VES-i nduced ERK activity and accompanied by activation of caspase-3. Inhibition of PKC by GF109203X blocked VES-mediated membrane translocation of PKC-a an d cleavage of caspase-3 cascade, resulting in prevention of VES-induced apo ptosis. On the contrary, PKC activation by cotreatment with LPC or thapsiga rgin and VES synergistically increased VES-mediated apoptosis. However, inh ibition of ERK activity by PD98059 showed no significant effect on VES-indu ced PKC activity and apoptosis. Taken together, our data suggest that VES i nduces activation of PKC and PKC-dependent hypophosphorylation of retinobla stoma protein, which results in induction of apoptosis, and that VES-induce d early activation of ERK and ERK-dependent induction of p21(WAF1) are not required for apoptosis. (C) 2001 Academic Press.