HMG-CoA reductase inhibitors inhibit rat propylthiouracil-induced goiter by modulating the ras-MAPK pathway.
The aim of this study was to evaluate in vivo the antiproliferative effect of an inhibitor of isoprenoids metabolism, lovastatin, in an experimental model of propylthiouracil-induced goiter. In thyroid cells, thyrotropin (TSH)-induced proliferation requires active isoprenoid synthesis, and the HMG-CoA reductase inhibitors have antiproliferative effects in vitro. Propylthiouracil treatment (PTU) of rats led to thyroid hypertrophy and hyperplasia by TSH-induced activation of the mitogen-activated protein kinase (MAPK) pathway. Immunohistochemistry showed an increased number of proliferating cell nuclear antigen (PCNA)-positive cells in the thyroid gland of PTU-treated rats. Moreover, the phosphorylation of ERK1 and ERK2 was increased in the extract from goiter tissue as compared with the thyroid tissue of untreated rats. To determine whether the inhibition of selected pro-survival pathways (i.e., p21ras-MAPK) was sufficient to affect goitrogenesis, thyroids from 12 PTU-treated rats were injected in vivo with an adenovirus transducing a dominant-negative ras gene (Rad-L61.S186) and another set of 12 rats were injected with a pharmacological inhibitor of MAPK (PD98059). Both Rad-L61.S186 and PD98059 were able to inhibit the PTU-induced goiter. It is interesting to note that lovastatin, when administered in drinking water, significantly prevented the thyroid gland enlargement. Therefore, lovastatin-treated thyroid glands were significantly smaller than those treated with PTU alone. In addition, the lovastatin-treated glands also showed a decreased expression of phosphorylated ERK1/2 and a number of PCNA-positive cells. Our data suggest that lovastatin is an efficient inhibitor of goitrogenesis and provide a rationale for innovative therapeutic strategies employing statins in the treatment of nodular goiter in humans.
Laezza
Chiara
C
Dipartimento di Scienze Farmaceutiche, Università di Salerno, Via Ponte Don Melillo, 84084, Fisciano, Salerno, Italy.
Mazziotti
Gherardo
G
Fiorentino
Laura
L
Gazzerro
Patrizia
P
Portella
Giuseppe
G
Gerbasio
Diego
D
Carella
Carlo
C
Matarese
Giuseppe
G
Bifulco
Maurizio
M
D000818:Animals; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D018014:Gene Transfer Techniques; D006042:Goiter / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006965:Hyperplasia; D006984:Hypertrophy; D008148:Lovastatin / Q000494:pharmacology* / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011441:Propylthiouracil; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013729:Terpenes / Q000378:metabolism; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013972:Thyrotropin / Q000097:blood; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D005419:Flavonoids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D047428:Protein Kinase Inhibitors; D013729:Terpenes; D011441:Propylthiouracil; D013972:Thyrotropin; D008148:Lovastatin; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one