Interferon-γ Sensitises Human Osteosarcoma Cells to Trail-mediated Apoptosis

Nearly half of all patients with osteosarcoma are still not cured by the currently employed multimodal treatment. New strategies are therefore needed to further improve the outcome. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2) is able to induce programmed cell death in transformed cells, while normal cells remain unaffected.

We have investigated the effect of TRAIL in combination with IFN-γ on four human osteosarcoma cell lines; Saos-2, U2OS, KPDXM and OHS, and on one normal human fibroblast cell line, MRC-5.

One of the four osteosarcoma cell lines was TRAIL-resistant, but was sensitised to TRAIL-mediated cell death upon pre-incubation with IFN-γ. In two of the three TRAIL-sensitive cell lines, the effect of TRAIL was enhanced by IFN-γ. The normal human fibroblast cell line MRC-5 was not affected by treatment with TRAIL and IFN-γ. A caspase cascade involving the activation of caspase-8, caspase-7 and PARP was associated with the onset of apoptosis in the osteosarcoma cell lines. Apoptosis was partly inhibited by the addition of caspase inhibitors zVADfmk (general inhibitor) and zIETDfmk (selective caspase-8 inhibitor). These findings further emphasize the important role of the caspases in cell death signalling.

Our results show that treatment with both IFN-γ and TRAIL efficiently induces cell death in osteosarcoma cell lines and should be further investigated as a potential future therapy.