TNF-related apoptosis-inducing ligand (TRAIL) is capable of causing apoptosis in
tumor cells but not in normal cells; however, it has been shown that certain types of
tumor cells are resistant to TRAIL-induced apoptosis. In this study, we examined the potentiation of TRAIL-induced apoptosis in the stromal-like
tumor cells of
giant cell tumor of bone (GCT). We show that both
mRNA and
protein of
TRAIL receptors-
death receptors (DR4, DR5) and decoy receptors (DcR1, DcR2) are present in GCT stromal
tumor cells. However, the expression profiles in all GCT clones tested do not readily correlate with their differential sensitivity to TRAIL. To this end, we selected
thapsigargin (TG), an agent known to cause perturbations in intracellular Ca(2+) homeostasis to enhance the apoptotic action of TRAIL. When added alone, neither TRAIL nor TG induces a therapeutically important magnitude of cell death in GCT
tumor cells. Interdependently, scheduled treatment of the cultures with TG followed by subsequent addition of TRAIL resulted in a significant synergistic apoptotic activity, while in contrast, no obvious augmentation was seen when TRAIL was added before TG. This effect was in accord with our observation that TG predominantly up-regulated both
mRNA and
protein expression of DR5, as well as DR4
mRNA while down-regulating DcR1
protein in GCT stromal-like
tumor cells. Taken together, our findings suggest that TG is able to sensitize
tumor cells of GCT to TRAIL-induced cell death, perhaps in part through up-regulating the
death receptor DR5 and down-regulating the decoy
receptor DcR1. These findings provide an additional insight into the design of new treatment modalities for patients suffering from GCT.