Interferon-gamma mediated up-regulation of caspase-8 sensitizes medulloblastoma cells to radio- and chemotherapy.
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-gamma mediated up-regulation of caspase-8 in human MB cells was found to result in chemosensitization 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-gamma mediated chemosensitization and radiosensitization effects were reduced by treatment with the caspase-8 specific inhibitor z-IETD-fmk. Treatment of IFN-gamma resulted in activation of STAT1 in DAOY MB cells and to a lesser extent in D425, but not in D341, indicating that IFN-gamma acts in MB cells through STAT1-dependent and -independent signalling pathways. Taken together, our results demonstrate that IFN-gamma mediated restoration of caspase-8 in MB cells might enhance apoptotic pathways relevant to the response to chemo- and radiotherapy.
Meister
N
N
Neuro-Oncology Program, University Children's Hospital of Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland.
Shalaby
T
T
von Bueren
A O
AO
Rivera
P
P
Patti
R
R
Oehler
C
C
Pruschy
M
M
Grotzer
M A
MA
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D002648:Child; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D008875:Middle Aged; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D007371:Interferon-gamma; D053181:Caspase 8