Potential mechanisms of resistance to TRAIL/Apo2L-induced apoptosis in human promyelocytic leukemia HL-60 cells during granulocytic differentiation

Human promyelocytic leukemia HL-60 cells are well known to differentiate in to granulocytes or monocytes in the presence of some agents such as DMSO or PMA, respectively. Differentiated HL-60 cells become resistant to some apo ptotic stimuli including anticancer drugs or irradiation though undifferent iated cells significantly respond to these stimuli. TRAIL (TNF-related apop tosis-inducing ligand) which is also known as Apo2 ligand (Apo2L), a new me mber of TNF family, can induce apoptosis in some tumor cells but not in man y normal cells. We show here that apoptosis is well induced in HL-60 cells by TRAIL, but susceptibility to TRAIL is reduced during granulocytic differ entiation by DMSO, We also suggest some possible mechanisms by which granul ocytic differentiated cells become resistant to TRAIL-induced apoptosis. Fi rst, in granulocytic differentiated cells, expression of antagonistic decoy receptors for TRAIL (TRAIL-R3/TRID/DcR1/LIT and TRAIL-R4/TRUNDD/DcR2) were enhanced. In addition, expression of Toso, a cell surface apoptosis regula tor, seemed to block activation of caspase-8 by TRAIL via enhanced expressi on of FLIPL in granulocytic differentiated cells. These findings suggest th at differentiated cells are resistant using plural mechanisms against Vario us apoptosis-inducing stimuli rather than undifferentiated cells.