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

Medulloblastoma is a malignant cerebellar tumor usually manifesting in chil dhood. We have previously shown that blocking the mevalonate pathway with l ovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, inhibits medulloblastoma proliferation and induces ap optosis in vitro. The underlying mechanism may involve blocking post-transl ational modification of important mitogenic signal-transduction proteins. W e show that p21 ras processing is blocked by lovastatin, suggesting that in hibition of isoprenylation may be important in lovastatin induced apoptosis . To test this hypothesis, manumycin A, an antibiotic which inhibits farnes yl protein transferase and thus farnesylation, was administered to 4 medull oblastoma cell lines in vitro. We found that blocking protein farnesylation with manumycin A was followed by apoptosis in a time- and dose-dependent m anner. However, cell death induced by manumycin A was uniformly more rapid and efficient, requiring only 12 to 24 hr of treatment, than lovastatin-ind uced apoptosis, which required 36 to 96 hr (depending on the cell line test ed). In addition, unlike lovastatin, which caused cell-cycle arrest in GI p hase and HMG-CoA reductase gene up-regulation, manumycin A had no effect on the cell cycle and resulted in down-regulation of HMG-CoA reductase gene e xpression. In both lovastatin- and manumycin A-treated cells, cellular cyst eine protease precursor (CPP32) was activated, confirming the occurrence of apoptosis. Int. J. Cancer 82:430-434, 1999. (C) 1999 Wiley-Liss, Inc.