DIFFERENTIAL-EFFECTS OF PHORBOL ESTER ON APOPTOSIS IN HL-60 PROMYELOCYTIC LEUKEMIA-CELLS

The role of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) in apoptosis of HL-60 cells was investigated. PMA inh ibited DNA fragmentation induced by thapsigargin (TG) and 4-bromo-calc ium ionophore (Br-A23187). The inhibitory effect of PMA was concentrat ion-related and was abolished by a specific PKC inhibitor, bisindolylm aleimide (GF109203X). In addition, TG-induced apoptosis was decreased in cells in which PKC activity was down-regulated by long-term pretrea tment with PMA. These results indicate that PKC activation by PMA inhi bits HL-60 cell apoptosis induced by TG and Br-A23187, and that this i nhibition is not influenced by the down-regulation of PKC. However, PM A did not inhibit DNA fragmentation induced by 1-beta-D-arabinofuranos ylcytosine (Ara-C) and cycbheximide. PMA suppressed TG- or Br-A23187-i nduced DNA fragmentation probably by interfering in the modulation of calcium homeostasis by TG and Br-A23187. Our results indicate that PKC participates in the regulation of apoptosis only by some pathways. Do wn-regulation of PKC is not responsible for the diverse effects of PKC activators on apoptosis. The effect of a PKC modulator on apoptosis i s dependent upon interaction with individual apoptotic stimulus.