Activation of the Hedgehog (Hh) pathway has been identified in several
cancers, including
medulloblastoma, but the mechanisms by which this pathway affects
tumor survival and growth are incompletely understood. We investigated whether Hedgehog might promote survival of
medulloblastoma cells via up-regulation of BclII. We found that
mRNA levels of the Hedgehog pathway effector Gli1 were significantly associated with BclII expression in
medulloblastoma and that Gli1 and BclII are both present in regions of decreased apoptosis in nodular
medulloblastoma. Transient overexpression of Gli1 and Gli2 in
medulloblastoma cultures induced a BclII transcriptional reporter and increased BclII
protein levels, whereas stable overexpression of Gli1 was associated with increased BclII
mRNA. The Hedgehog antagonist
cyclopamine blocked expression of the Hh pathway targets PTCH1 and Gli1, lowered BclII levels, and increased apoptosis in DAOY and UW228
medulloblastoma cells. Apoptotic induction caused by
cyclopamine could be rescued in part by enforced expression of Gli1 or BclII. Hh pathway blockade also sensitized
medulloblastoma to the effects of the proapoptotic agent
lovastatin. These data demonstrate that BclII is an important mediator of Hh activity in
medulloblastoma and suggest new strategies for combined chemotherapeutic regimens.