Inhibition of farnesylation blocks growth but not differentiation in FRTL-5 thyroid cells

The cholesterol lowering drug lovastatin, a competitive inhibitor of 3-hydr oxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, blocks DNA synthesis a nd proliferation of thyrotropin (TSH) primed FRTL-5 rat thyroid cells. The blockade can be completely prevented and/or reversed by mevalonate and larg ely prevented and/or reversed by farnesol whereas cholesterol and/or other non-sterol mevalonate derivatives such as ubiquinone, dolichol or isopenten yladenosine are ineffective. TSH-dependent augmentation of cyclic-AMP and c AMP dependent differentiated functions, such as iodide uptake, are unaffect ed by lovastatin. H-3-Thymidine incorporation into DNA is also decreased by alpha-hydroxyfarnesyl-phosphonic acid, an inhibitor of protein farnesylati on which mimicks the effect of lovastatin since it also leaves unaffected T SH stimulated iodide uptake. It is suggested that the HMG-CoA reductase inh ibitor lovastatin affects cell proliferation mainly through inhibition of p rotein farnesylation which results in altered function proteins relevant fo r proliferation control, notably p21(ras) and/or other small GTPases. (C) S ociete francaise de biochimie et biologie moleculaire / Elsevier, Paris.