Igf-I influences everolimus activity in medullary thyroid carcinoma.

Erica Gentilin,Teresa Gagliano,Roberta Rossi,Maria Chiara Zatelli,Martina Rossi,Federico Tagliati,Isabella Merante Boschin,Carmelina Di Pasquale,Ettore C Degli Uberti,Mariarosa Pelizzo

doi:10.3389/fendo.2015.00063

Erica Gentilin, Teresa Gagliano + Show 8 more

Open Access

https://doi.org/10.3389/fendo.2015.00063

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Abstract

Medullary thyroid carcinoma (MTC) is a rare tumor originating from thyroid parafollicular C cells. It has been previously demonstrated that insulin-like growth factor I (IGF-I) protects MTC from the effects of antiproliferative drugs. Everolimus, an mTOR inhibitor, has shown potent antiproliferative effects in a human MTC cell line, TT, and in two human MTC primary cultures. To verify whether IGF-I may influence the effects of everolimus in a group of human MTC primary cultures. We collected 18 MTCs that were dispersed in primary cultures, treated without or with 10 nM-1 μM everolimus and/or 50 nM IGF-I. Cell viability was evaluated after 48 h, and calcitonin (CT) secretion was assessed after a 6 h incubation. IGF-I receptor downstream signaling protein expression profile was also investigated. Everolimus significantly reduced cell viability in eight MTC [by ~20%; P < 0.01 vs. control; everolimus-responders (E-R) MTCs], while cell viability did not change in 10 MTCs [everolimus-non-responders (E-NR) MTCs]. In E-R MTCs, IGF-I blocked the antiproliferative effects of everolimus that did not affect CT secretion, but blocked the stimulatory effects of IGF-I on this parameter. IGF-I receptor downstream signaling proteins were expressed at higher levels in E-NR MTC as compared to E-R MTCs. IGF-I protects a subset of MTC primary cultures from the antiproliferative effects of everolimus and stimulates CT secretion by an mTOR mediated pathway that, in turn, may represent a therapeutic target in the treatment of aggressive MTCs.

Highlights

Insulin-like growth factor I (IGF-I) system has been described in both rat [1] and human medullary thyroid carcinoma (MTC) [2], where it stimulates DNA synthesis [3]
It has been recently demonstrated that everolimus inhibits cell viability in a doseand time-dependent fashion and reduces mTOR phosphorylation in a human MTC cell line and in two human MTC primary cultures [12]
Effects of Everolimus on Cell Viability To determine the effects of everolimus on cell viability of dispersed MTC cells, we assessed cell viability in MTC primary cultures after a 48 h treatment with 10 nM–1 μM everolimus

Summary

Introduction

Insulin-like growth factor I (IGF-I) system has been described in both rat [1] and human medullary thyroid carcinoma (MTC) [2], where it stimulates DNA synthesis [3]. It has been previously demonstrated that IGF-I protects TT cells from drug-induced cytotoxicity [5]. IGF-I may hamper the effects of antiproliferative drugs in MTC. An alternative medical approach for neuroendocrine tumors, including MTC, is represented by mTOR inhibitors, such as everolimus. The latter displays antiproliferative effects on a wide spectrum of tumors including neuroendocrine tumors, both in vitro and in vivo [7,8,9,10,11]. The variable effects of mTOR inhibitors may be ascribed to independent signaling mechanisms, activated by several growth factors, including IGF-I

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