HMG-CoA reductase inhibitors inhibit rat propylthiouracil-induced goiter by modulating the ras-MAPK pathway

Abstract

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.

Extracellular superoxide dismutase is a thyroid differentiation marker down-regulated in cancer

“…PTU treatment is known to cause decreased T 3 production with subsequent increase in TSH, thyroid enlargement, and activated thyroid function (Levey 1963, al-Alawi et al 1995, Laezza et al 2006; we therefore treated four rats with PTU ad libitum and killed the animals after 2 weeks to isolate the thyroids. As shown in Fig.…”

Do Statins Affect Thyroid Volume and Nodule Size in Patients with Hyperlipidemia in a Region with Mild-to-Moderate Iodine Deficiency? A Prospective Study

“…In a 2006 study conducted on rats, Laezza et al [15] reported that HMG-CoA reductase inhibitors inhibited propylthiouracyl-induced goiter by p21 ras-MAPK pathway modulation. Even though different molecular and genetic processes have been proposed, results show that lovastatin is an effective inhibitor in goitrogenesis with p21 ras farnesylation inhibition.…”

“…Ras mutation activation and other oncogenes are common in thyroid tumors; ras mutations may also be present in nodular hyperplasia of the thyroid [13, 14]. In a 2006 study performed on rats, Laezza et al [15] showed that HMG-CoA reductase inhibitors inhibit propylthiouracil-induced goiter with p21 ras-MAPK (mitogen-activated protein kinase) pathway modulation. Thus, statins may offer a new treatment alternative for benign and malignant proliferative thyroid diseases.…”

Comparative Efficacy and Toxicity of Different Species of Sargassum in Haizao Yuhu Decoction in PTU‐Induced Goiter Rats

“…After 3 days of acclimatization, the rats were randomly divided into 5 groups: normal, model, Euthyrox, HYDf, and HYDp groups; all rats except those in the normal control group received intragastric administration of PTU at a dosage of 0.01 g/kg daily for 14 days to induce the goitrous model according to previously reports [15] and were given different treatments for 28 days, as shown in Table 2.…”