Published online before print April 13, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.060993

Article

Interferon- Sensitizes Resistant Ewing's Sarcoma Cells to Tumor Necrosis Factor Apoptosis-Inducing Ligand-Induced Apoptosis by Up-Regulation of Caspase-8 Without Altering Chemosensitivity

Andrej Lissat^*, Thomas Vraetz^*, Maria Tsokos, Ruth Klein^*, Matthias Braun^*, Nino Koutelia^*, Paul Fisch, Maria E. Romero, Lauren Long, Peter Noellke^*, Crystal L. Mackall, Charlotte M. Niemeyer^*, and Udo Kontny^*@

From the Division of Pediatric Hematology and Oncology,* Department of Pediatrics and Adolescent Medicine, and the Institute of Pathology, Albert-Ludwigs-University, Freiburg, Germany; the Laboratory of Pathology, and the Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

^@ To whom correspondence should be addressed. E-mail: udo.kontny{at}uniklinik-freiburg.de.

	Abstract

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- 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- 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 that 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- 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- in upcoming clinical trials with TRAIL.