Mevalonate prevents lovastatin-induced apoptosis in medulloblastoma cell lines.
BACKGROUND
3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) is a key rate-limiting enzyme in the mevalonate pathway, which generates precursors for cholesterol biosynthesis and the production of non-steroidal mevalonate derivatives that are involved in a number of growth-regulatory processes. We have reported that lovastatin, a competitive inhibitor of HMG-CoA reductase, not only inhibits medulloblastoma proliferation in vitro, but also induces near-complete cell death via apoptosis. The present study explores some of the pathways which may be involved in lovastatin-induced apoptosis.


METHODS
Medulloblastoma cell lines were exposed in vitro to lovastatin with or without mevalonate, and document the effects using morphology, flow cytometry. DNA electrophoresis and Northern analysis.


RESULTS
1) Mevalonate prevents apoptosis when co-incubated with lovastatin, or when administered to lovastatin-pretreated cells. 2) Mevalonate restores the lovastatin-arrested cell cycle, allowing S phase entry. 3) Mevalonate does not prevent lovastatin-induced apoptosis after a critical duration of lovastatin pretreatment. For cell lines Daoy and UW228 this was 24 hours, and for D283 Med and D341 Med it was 48 hours. 4) Increases in HMG-CoA reductase mRNA levels induced by lovastatin are abrogated by co-incubation with lovastatin and mevalonate.


CONCLUSIONS
These results confirm that lovastatin inhibition of this enzyme results in blockage of the mevalonate pathway, and that such a block is a critical step in the mechanism of lovastatin-induced apoptosis.
Wang
W
W
Department of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
Macaulay
R J
RJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015152:Blotting, Northern; D048429:Cell Size / Q000187:drug effects; D004273:DNA, Neoplasm / Q000032:analysis; D004347:Drug Interactions; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology*; D008527:Medulloblastoma; D008798:Mevalonic Acid / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid