Selective inhibition of apoptosis by TPA-induced differentiation of U937 leukemic cells

U937 leukemic cells treated for 24 h with 16 nM 12-O-tetradecanoylphorbol 1 3-acetate (TPA), that induces their macrophagic terminal differentiation, b ecome resistant to etoposide-induced apoptosis, Exposure of undifferentiate d U937 cells to 50 mu M etoposide for 6 h,that triggers apoptosis in 80% ce lls, activates procaspase-2L, -3 and -8, induces the mitochondrial release of cytochrome c and decreases Mcl-1 expression without modifying Bcl-2, Bcl -xL and Bar protein levels. All these events are inhibited in TPA-different iated U937 cells that are also resistant to vinblastine-induced and Fas-med iated cell death, Interestingly, these cells are not inherently resistant t o apoptosis induction, Exposure of TPA-differentiated U937 cells to 0.8 mu g/ml cycloheximide for 24 h, that triggers apoptosis in 50% cells, activate s procaspase-2L, -3 and -8, induces the mitochondrial release of cytochrome c and decreases Bcl-xL expression without modifying Bcl-2, Mcl-1 and Bar p rotein levels. All these events are not observed in undifferentiated cells treated in similar conditions. These results indicate that the apoptotic pa thway that involves the release of cytochrome c from mitochondria and the c leavage of procaspases remains functional in TPA-differentiated cells.