Inhibition of growth factor signaling pathways by lovastatin.
Human fibroblasts treated with the antihypercholesterolaemic drug, lovastatin, displayed a diminished signaling response to epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). Supplementing the culture medium with mevalonic acid restored the signaling response. Not all growth factor signaling pathways were impaired, however, as platelet-derived growth factor (PDGF-BB) and basic fibroblast growth factor (bFGF) responses were refractory to lovastatin treatment. These results suggest the involvement of product(s) of mevalonate metabolism (e.g., prenylated proteins such as p21ras or G proteins) in the signal transduction of EGF, insulin and IGF-I. The inhibition of cell growth by lovastatin may be caused by the inability of the cell to enter the S phase of the cell cycle due to obstruction of the signaling of progression factors.
Vincent
T S
TS
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston.
Wülfert
E
E
Merler
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D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007231:Infant, Newborn; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin; D013936:Thymidine / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D006133:Growth Substances; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D008148:Lovastatin; D008798:Mevalonic Acid; D013936:Thymidine