Apoptosis of medulloblastoma cells in vitro follows inhibition of farnesylation using manumycin A.

摘要: Medulloblastoma is a malignant cerebellar tumor usually manifesting in childhood. We have previously shown that blocking the mevalonate pathway with lovastatin, competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, inhibits medulloblastoma proliferation and induces apoptosis vitro. The underlying mechanism may involve post-translational modification important mitogenic signal-transduction proteins. show p21 ras processing blocked by suggesting inhibition isoprenylation be lovastatin-induced apoptosis. To test this hypothesis, manumycin A, an antibiotic which farnesyl protein transferase thus farnesylation, was administered to 4 cell lines found farnesylation followed time- dose-dependent manner. However, death induced uniformly more rapid efficient, requiring only 12 24 hr treatment, than apoptosis, required 36 96 (depending on line tested). In addition, unlike caused cell-cycle arrest G1 phase HMG-CoA reductase gene up-regulation, had no effect cycle resulted down-regulation expression. both lovastatin- A-treated cells, cellular cysteine protease precursor (CPP32) activated, confirming occurrence