Although TNF-related apoptosis-inducing ligand (TRAIL) usually induces cell death
in tumor cells, there are some tumor cell types that are resistant to its
apoptogenic effects. Some chemotherapeutic drugs, however, can sensitize
resistant cancer cells to TRAIL by either upregulating surface TRAIL death
receptor expression or by modulating intracellular signalling pathways emanating
from TRAIL receptors. U2OS human osteosarcoma cells express TRAIL-R2 but are
resistant to TRAIL-induced apoptosis. however, the genotoxic drugs, Doxorubicin
and Cisplatin, are able to sensitize U2OS cells to TRAIL, without affecting their
surface expression of either death or decoy TRAIL receptors. We demonstrate that
Doxorubicin and Cisplatin downmodulate X-IAP, while not affecting FLIP levels in
U2OS cells. Selective downmodulation of X-IAP protein synthesis by specific small
interference RNA transfection induced a sensitization of U2OS cells to TRAIL
comparable to that induced by pharmacological treatment with genotoxic drugs.
TRAIL-R2 downmodulation by siRNAs completely abolished the TRAIL-induced
apoptosis of genotoxin-treated U2OS cells. Our findings demonstrate that
Doxorubicin and Cisplatin do not sensitize U2OS osteosarcoma cells to TRAIL by
surface receptor modulation but rather by the removal of the intracellular
signalling inhibition generated by X-IAP, suggesting a foreseeable relevant
advantage to the therapy of these tumors by the combined regimen of
genotoxin-based chemotherapy and TRAIL