Transglutaminase 2 expression levels regulate sensitivity to cystamine plus TRAIL-mediated apoptosis

In this study, we demonstrate for the first time that cystamine, an inhibitor of transglutaminase 2 (TG2), enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in Caki cells, but not in normal human mesangial cells. Cystamine plus TRAIL-induced down-regulation of c-FLIP was recovered to basal levels by addition of the pancaspase inhibitor, z-VAD. The forced expression of c-FLIP attenuated cystamine plus TRAIL-mediated apoptosis in Caki cells. Although, cells expressing high levels of TG2 were more sensitive to cystamine plus TRAIL-mediated apoptosis than were cells expressing low levels of TG2, cystamine plus TRAIL-mediated apoptosis in the cell line expressing high levels of TG2 was reduced when TG2 levels were knocked down with siRNA. These results indicate that the level of TG2 modulates cystamine plus TRAIL-induced apoptosis. Taken together, the present findings suggest that cystamine may be an effective sensitizer of TRAIL-induced apoptosis in cancer cells expressing high levels of TG2.