Cytotoxic Effects of Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)and its Molecular Mechanism in Human Gastric Cancer Cells / 대한해부학회지

ABSTRACT

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)induces apoptosis in some cancer cells such as breast,prostate,lung,and colon cancer cells,but not normal cells.However,because the effects of TRAIL in gastric cancer cells is unclear,we undertook this study to clarify the effects of TRAIL and its mechanism. To assess the cytotoxicity of TRAIL,two human gastric cancer cell lines,SNU-484 and SNU601,were treated with TRAIL (0-200 ng/mL)in the presence or absence of cycloheximide (1 microgram/mL)for 24 h.Both SNU-484 and SNU-601 were sensitive to TRAIL-induced cell death in a dose-dependent manner.The combination of TRAIL (100 ng/mL)and cycloheximide (1 microgram/mL)for 24 h enhanced cell death and PARP cleavage by promoting activations of caspase-8, caspase-9,and caspase-3,relative to that of TRAIL alone.We further examined the expressions of death receptor 4 (DR4),death receptor 5 (DR5),and FLICE inhibitory protein (FLIP).Although DR4 and DR5 were expressed in both cell lines,the expression of long form (FLIPL )and short form (FLIPS )of FLIP were detected at the low levels. Overexpression of FLIPL or FLIPS in both cell lines rendered the cells resistant to TRAIL.Taken together,our results suggest that FLIP promotes human gastric cancer cell survival against TRAIL-induced apoptosis and is important modulator for TRAIL-induced cell death in human gastric cancer cells.