Interferon‐γ sensitizes osteosarcoma cells to fas‐induced apoptosis by up‐regulating fas receptors and caspase‐8

Authors:
  • YRYaddanapudi Ravindranath
    Yaddanapudi Ravindranath
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Abstract
Background: Osteosarcoma is the third most frequent neoplasm in adolescents. Although chemotherapy, frequently used in pre‐ and post‐operative settings, has resulted in significant improvement in disease‐free survival, some patients show little sensitivity to chemotherapy and alternative therapeutic strategies are needed. Because the Fas ligand/Fas receptor (CD95, APO‐1) apoptosis pathway is a potential therapeutic target in osteosarcomas, we examined the effect of IFN‐γ on Fas‐induced apoptosis in four osteosarcoma cell lines.Procedure and Results: As measured by flow cytometry, all cell lines expressed cell surface IFN‐γ receptors, and when cultured for 2 days in the presence of IFN‐γ, all cell lines exhibited a significant increase in expression of Fas receptors. By flow cytometric detection of intracellular fragmented DNA as a marker of apoptosis, all cell lines cultured with either IFN‐γ or anti‐Fas antibody (clone CH‐11) alone showed only moderate apoptosis, whereas significantly high levels of apoptosis occurred in cells cultured with both IFN‐γ and CH‐11. Western blotting analysis also revealed that IFN‐γ caused up‐regulation of caspase‐8 in all cell lines, but no change in Fas‐associated death domain protein (FADD/MORT1) or caspase‐3. Both caspase‐8 and caspase‐3 were activated when apoptosis was induced with both IFN‐γ and CH‐11. Addition to cultures of z‐IETD‐fmk, an inhibitor of caspase‐8, significantly blocked this apoptosis.Conclusions: IFN‐γ sensitizes osteosarcoma cells to Fas‐induced apoptosis through up‐regulation of Fas receptor and caspase‐8. Combined immunotherapy with IFN‐γ and either anti‐Fas monoclonal antibody or cytotoxic T cells that bear Fas ligand might be a useful adjunctive therapy for patients with osteosarcoma.

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