Interferon-γ mediated up-regulation of caspase-8 sensitises medulloblastoma cells to radio- and chemotherapy

Abstract

Loss of caspase-8 expression – which has been demonstrated in a subset of Medulloblastoma (MB) – might block important apoptotic signalling pathways and therefore contribute to treatment resistance. In this study, IFN-γ mediated up-regulation of caspase-8 in human MB cells was found to result in chemosensitisation to cisplatin, doxorubicin and etoposide, and sensitisation to radiation. These effects were more prominent in D425 and D341 MB cells (low basal caspase-8 expression) when compared to DAOY MB cells (high basal caspase-8 expression). IFN-γ mediated chemosensitisation and radiosensitisation effects were reduced by treatment with the caspase-8 specific inhibitor z-IETD-fmk. Treatment of IFN-γ resulted in activation of STAT1 in DAOY MB cells and to a lesser extent in D425, but not in D341, indicating that IFN-γ acts in MB cells through STAT1-dependent and -independent signalling pathways. Taken together, our results demonstrate that IFN-γ mediated restoration of caspase-8 in MB cells might enhance apoptotic pathways relevant to the response to chemo- and radiotherapy.