Premium
Apoptosis of medulloblastoma cells In vitro follows inhibition of farnesylation using manumycin A
Author(s) -
Wang Wei,
MaCaulay Robert J.B.
Publication year - 1999
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19990730)82:3<430::aid-ijc17>3.0.co;2-9
Subject(s) - lovastatin , prenylation , apoptosis , farnesyltransferase inhibitor , biology , hmg coa reductase , medulloblastoma , cell cycle , reductase , cell growth , cancer research , cell cycle checkpoint , in vitro , microbiology and biotechnology , biochemistry , farnesyltransferase , enzyme , cholesterol
Medulloblastoma is a malignant cerebellar tumor usually manifesting in childhood. We have previously shown that blocking the mevalonate pathway with lovastatin, a competitive inhibitor of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase, inhibits medulloblastoma proliferation and induces apoptosis in vitro . The underlying mechanism may involve blocking post‐translational modification of important mitogenic signal‐transduction proteins. We show that p21 ras processing is blocked by lovastatin, suggesting that inhibition of isoprenylation may be important in lovastatin‐induced apoptosis. To test this hypothesis, manumycin A, an antibiotic which inhibits farnesyl protein transferase and thus farnesylation, was administered to 4 medulloblastoma cell lines in vitro . We found that blocking protein farnesylation with manumycin A was followed by apoptosis in a time‐ and dose‐dependent manner. However, cell death induced by manumycin A was uniformly more rapid and efficient, requiring only 12 to 24 hr of treatment, than lovastatin‐induced apoptosis, which required 36 to 96 hr (depending on the cell line tested). In addition, unlike lovastatin, which caused cell‐cycle arrest in G 1 phase 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 expression. In both lovastatin‐ and manumycin A‐treated cells, cellular cysteine protease precursor (CPP32) was activated, confirming the occurrence of apoptosis. Int. J. Cancer 82:430–434, 1999. © 1999 Wiley‐Liss, Inc.