TY - JOUR
T1 - Interferon-γ sensitizes resistant Ewing's sarcoma cells to tumor necrosis factor apoptosis-inducing ligand-induced apoptosis by up-regulation of caspase-8 without altering chemosensitivity
AU - Lissat, Andrej
AU - Vraetz, Thomas
AU - Tsokos, Maria
AU - Klein, Ruth
AU - Braun, Matthias
AU - Koutelia, Nino
AU - Fisch, Paul
AU - Romero, Maria E.
AU - Long, Lauren
AU - Noellke, Peter
AU - Mackall, Crystal L.
AU - Niemeyer, Charlotte M.
AU - Kontny, Udo
N1 - Funding Information:
Supported by the Clotten Stiftung, Freiburg, Germany, the Intramural Research Program of the National Cancer Institute, and by a fellowship from the Kind-Philipp-Stiftung of the Stifterverband für die Deutsche Wissenschaft (to N.K.).
PY - 2007/6
Y1 - 2007/6
N2 - Ewing's sarcoma cells are highly susceptible to apoptosis via tumor necrosis factor apoptosis-inducing ligand (TRAIL). Resistance to TRAIL has been linked to deficient expression of caspase-8 in vitro. Here, we report on the status of caspase-8 expression in tumors from patients with Ewing's sarcoma, the effect of interferon-γ on caspase-8 expression and apoptosis, and the role of caspase-8 for TRAIL- and chemotherapy-mediated apoptosis in Ewing's sarcoma. Using immunohistochemistry, we show that low expression of caspase-8 is seen in about 24% of tumors. Interferon-γ induces expression of caspase-8 at concentrations achievable in humans and sensitizes cells to TRAIL. Transfection of wild type but not mutant caspase-8 into caspase-8-deficient Ewing's sarcoma cells restored sensitivity to TRAIL, indicating diat up-regulation of caspase-8 is sufficient to restore TRAIL sensitivity. In contrast, no role for caspase-8 in chemotherapy-induced apoptosis was identified, because 1) transfection of caspase-8 or treatment with interferon-γ did not alter the sensitivity of caspase-8-deficient cells to chemotherapeutics, 2) application of chemotherapy did not select for caspase-8-negative tumor cells in vivo, and 3) the caspase-8 status of tumors did not influence survival after chemotherapy-based protocols. In conclusion, our data provide a rationale for the inclusion of interferon-γ in upcoming clinical trials with TRAIL.
AB - Ewing's sarcoma cells are highly susceptible to apoptosis via tumor necrosis factor apoptosis-inducing ligand (TRAIL). Resistance to TRAIL has been linked to deficient expression of caspase-8 in vitro. Here, we report on the status of caspase-8 expression in tumors from patients with Ewing's sarcoma, the effect of interferon-γ on caspase-8 expression and apoptosis, and the role of caspase-8 for TRAIL- and chemotherapy-mediated apoptosis in Ewing's sarcoma. Using immunohistochemistry, we show that low expression of caspase-8 is seen in about 24% of tumors. Interferon-γ induces expression of caspase-8 at concentrations achievable in humans and sensitizes cells to TRAIL. Transfection of wild type but not mutant caspase-8 into caspase-8-deficient Ewing's sarcoma cells restored sensitivity to TRAIL, indicating diat up-regulation of caspase-8 is sufficient to restore TRAIL sensitivity. In contrast, no role for caspase-8 in chemotherapy-induced apoptosis was identified, because 1) transfection of caspase-8 or treatment with interferon-γ did not alter the sensitivity of caspase-8-deficient cells to chemotherapeutics, 2) application of chemotherapy did not select for caspase-8-negative tumor cells in vivo, and 3) the caspase-8 status of tumors did not influence survival after chemotherapy-based protocols. In conclusion, our data provide a rationale for the inclusion of interferon-γ in upcoming clinical trials with TRAIL.
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U2 - 10.2353/ajpath.2007.060993
DO - 10.2353/ajpath.2007.060993
M3 - Article
C2 - 17525260
AN - SCOPUS:34447295403
SN - 0002-9440
VL - 170
SP - 1917
EP - 1930
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -