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

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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.

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Acknowledgements

This investigation was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC), and from Educazione e Ricerca Medica Salernitana (ERMES). We thank Prof. Bruno Moncharmont for critically reading the manuscript.

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Authors and Affiliations

  1. Dipartimento di Scienze Farmaceutiche, Università di Salerno, Via Ponte Don Melillo, 84084, Fisciano, Salerno, Italy

    Chiara Laezza, Laura Fiorentino, Patrizia Gazzerro & Maurizio Bifulco

  2. Istituto di Endocrinologia e Oncologia Sperimentale CNR, Naples, Italy

    Chiara Laezza, Gherardo Mazziotti, Laura Fiorentino & Giuseppe Matarese

  3. Dipartimento di Medicina sperimentale e clinica “F. Magrassi” e A. Lanzara, Seconda Università degli studi di Napoli, Naples, Italy

    Gherardo Mazziotti & Carlo Carella

  4. Dipartimento di Biologia e Patologia cellulare e molecolare, Università degli studi di Napoli “Federico II”, Naples, Italy

    Chiara Laezza, Gherardo Mazziotti, Laura Fiorentino & Giuseppe Portella

  5. Dipartimento di Scienze Biomorfologiche e Funzionali, Università degli studi di Napoli “Federico II”, Naples, Italy

    Diego Gerbasio

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  1. Chiara Laezza
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Correspondence to Maurizio Bifulco.

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Chiara Laezza and Gherardo Mazziotti contributed equally to this paper.

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Laezza, C., Mazziotti, G., Fiorentino, L. et al. HMG-CoA reductase inhibitors inhibit rat propylthiouracil-induced goiter by modulating the ras-MAPK pathway. J Mol Med 84, 967–973 (2006). https://doi.org/10.1007/s00109-006-0079-8

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  • DOI: https://doi.org/10.1007/s00109-006-0079-8

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