Differential susceptibility of gastric cancer cells to TRAIL-induced apoptosis

Abstract

Understanding the molecular basis of the differential sensitivity of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis is required to predict therapeutic outcomes and to improve the effectiveness of TRAIL-based therapy. This study aimed to compare the responsiveness of gastric cancer cells to TRAIL treatment and to investigate the molecular basis of the differential TRAIL sensitivity of four gastric cancer cell lines. The TRAIL sensitivity of the four cell lines was ranked in the following order: SNU-16 ≈ SNU-620 > SNU-5 >> SNU-1. The level of AnnexinV binding and the activation profile of caspase-3, -8 and -9 corroborated the differential TRAIL susceptibility of the cell lines. To determine the molecular basis of the differential sensitivity to TRAIL, we examined the expression of signaling components involved in TRAIL-mediated apoptosis. The mRNA level and surface expression of death receptor4 (DR4) were significantly decreased in the SNU-1 cells compared to the other cell lines. Bid cleavage and X-linked inhibitor of apoptosis (XIAP) degradation were significantly increased in the SNU-16 and SNU-620 cells compared to the SNU-5 and SNU-1 cells, although Bid and XIAP were expressed at similar levels across the four cell lines. The expression and degradation of FLICE-inhibitory protein (FLIP) upon TRAIL treatment was independent of TRAIL sensitivity. In conclusion, the differential susceptibility of the four gastric cancer cells to TRAIL may be ascribed to the differential expression of DR4 and the proper augmentation of the death signal by the truncation of Bid and degradation of XIAP.