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Maria Cristina De Martino Division of Endocrinology, Department of Molecular and Clinical Endocrinology and Oncology, Department of Internal Medicine, Room Ee530b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands
Division of Endocrinology, Department of Molecular and Clinical Endocrinology and Oncology, Department of Internal Medicine, Room Ee530b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Peter M van Koetsveld Division of Endocrinology, Department of Molecular and Clinical Endocrinology and Oncology, Department of Internal Medicine, Room Ee530b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Richard A Feelders Division of Endocrinology, Department of Molecular and Clinical Endocrinology and Oncology, Department of Internal Medicine, Room Ee530b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Diana Sprij-Mooij Division of Endocrinology, Department of Molecular and Clinical Endocrinology and Oncology, Department of Internal Medicine, Room Ee530b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Marlijn Waaijers Division of Endocrinology, Department of Molecular and Clinical Endocrinology and Oncology, Department of Internal Medicine, Room Ee530b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Steven W J Lamberts Division of Endocrinology, Department of Molecular and Clinical Endocrinology and Oncology, Department of Internal Medicine, Room Ee530b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Wouter W de Herder Division of Endocrinology, Department of Molecular and Clinical Endocrinology and Oncology, Department of Internal Medicine, Room Ee530b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Annamaria Colao Division of Endocrinology, Department of Molecular and Clinical Endocrinology and Oncology, Department of Internal Medicine, Room Ee530b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Rosario Pivonello Division of Endocrinology, Department of Molecular and Clinical Endocrinology and Oncology, Department of Internal Medicine, Room Ee530b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Leo J Hofland Division of Endocrinology, Department of Molecular and Clinical Endocrinology and Oncology, Department of Internal Medicine, Room Ee530b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Patients with adrenocortical carcinoma (ACC) need new treatment options. The aim of this study was to evaluate the effects of the mTOR inhibitors sirolimus and temsirolimus on human ACC cell growth and cortisol production. In H295, HAC15, and SW13 cells, we have evaluated mTOR, IGF2, and IGF1 receptor expressions; the effects of sirolimus and temsirolimus on cell growth; and the effects of sirolimus on apoptosis, cell cycle, and cortisol production. Moreover, the effects of sirolimus on basal and IGF2-stimulated H295 cell colony growth and on basal and IGF1-stimulated phospho-AKT, phospho-S6K1, and phospho-ERK in H295 and SW13 were studied. Finally, we have evaluated the effects of combination treatment of sirolimus with an IGF2-neutralizing antibody. We have found that H295 and HAC15 expressed IGF2 at a >1800-fold higher level than SW13. mTOR inhibitors suppressed cell growth in a dose-/time-dependent manner in all cell lines. SW13 were the most sensitive to these effects. Sirolimus inhibited H295 colony surviving fraction and size. These effects were not antagonized by IGF2, suggesting the involvement of other autocrine regulators of mTOR pathways. In H295, sirolimus activated escape pathways. The blocking of endogenously produced IGF2 increased the antiproliferative effects of sirolimus on H295. Cortisol production by H295 and HAC15 was inhibited by sirolimus. The current study demonstrates that mTOR inhibitors inhibit the proliferation and cortisol production in ACC cells. Different ACC cells have different sensitivity to the mTOR inhibitors. mTOR could be a target for the treatment of human ACCs, but variable responses might be expected. In selected cases of ACC, the combined targeting of mTOR and IGF2 could have greater effects than mTOR inhibitors alone.

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Peter M van Koetsveld Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Giovanni Vitale Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands
Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands
Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Richard A Feelders Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Marlijn Waaijers Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Diana M Sprij-Mooij Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Ronald R de Krijger Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Ernst-Jan M Speel Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Johannes Hofland Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Steven W J Lamberts Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Wouter W de Herder Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Leo J Hofland Division of Endocrinology, Department of Pathology, Dipartimento di Scienze Mediche, IRCCS Istituto Auxologico Italiano, Department of Pathology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

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Adrenocortical carcinoma (ACC) is an aggressive tumor with very poor prognosis. Novel medical treatment opportunities are required. We investigated the effects of interferon-β (IFN-β), alone or in combination with mitotane, on cell growth and cortisol secretion in primary cultures of 13 human ACCs, three adrenal hyperplasias, three adrenal adenomas, and in two ACC cell lines. Moreover, the interrelationship between the effects of IGF2 and IFN-β was evaluated. Mitotane inhibited cell total DNA content/well (representing cell number) in 7/11 (IC50: 38±9.2 μM) and cortisol secretion in 5/5 ACC cultures (IC50: 4.5±0.1 μM). IFN-β reduced cell number in 10/11 (IC50: 83±18 IU/ml) and cortisol secretion in 5/5 ACC cultures (IC50: 7.3±1.5 IU/ml). The effect of IFN-β on cell number included the induction of apoptosis. IFN-β strongly inhibited mRNA expression of STAR, CYP11A1, CYP17A1, and CYP11B1. Mitotane and IFN-β induced an additive inhibitory effect on cell number and cortisol secretion. IGF2 (10 nM) inhibited apoptosis and increased cell number and cortisol secretion. These effects were counteracted by IFN-β treatment. Finally, IFN-β inhibited IGF2 secretion and mRNA expression. In conclusion, IFN-β is a potent inhibitor of ACC cell growth in human primary ACC cultures, partially mediated by an inhibition of the effects of IGF2, as well as its production. The increased sensitivity of ACC cells to mitotane induced by treatment with IFN-β may open the opportunity for combined treatment regimens with lower mitotane doses. The inhibition of the expression of steroidogenic enzymes by IFN-β is a novel mechanism that may explain its inhibitory effect on cortisol production.

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Maria Cristina De Martino
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Richard A Feelders
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Wouter W de Herder
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Peter M van Koetsveld
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Fadime Dogan
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Joseph A M J L Janssen
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A Marlijn Waaijers
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Claudia Pivonello Department of Internal Medicine Division of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands

Dipartimento di Medicina Clinica e Chirurgia Sezione di Endocrinologia, Università Federico II, Naples, Italy

Department of Pathology Erasmus Medical Center, Rotterdam and Reinier de Graaf Gasthuis, Delft, The Netherlands

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Steven W J Lamberts
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Annamaria Colao Department of Internal Medicine Division of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands

Dipartimento di Medicina Clinica e Chirurgia Sezione di Endocrinologia, Università Federico II, Naples, Italy

Department of Pathology Erasmus Medical Center, Rotterdam and Reinier de Graaf Gasthuis, Delft, The Netherlands

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Ronald R de Krijger Department of Internal Medicine Division of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands

Dipartimento di Medicina Clinica e Chirurgia Sezione di Endocrinologia, Università Federico II, Naples, Italy

Department of Pathology Erasmus Medical Center, Rotterdam and Reinier de Graaf Gasthuis, Delft, The Netherlands

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Rosario Pivonello Department of Internal Medicine Division of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands

Dipartimento di Medicina Clinica e Chirurgia Sezione di Endocrinologia, Università Federico II, Naples, Italy

Department of Pathology Erasmus Medical Center, Rotterdam and Reinier de Graaf Gasthuis, Delft, The Netherlands

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Leo J Hofland
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The mTOR pathway has recently been suggested as a new potential target for therapy in adrenocortical carcinomas (ACCs). The aim of the current study is to describe the expression of the mTOR pathway in normal adrenals (NAs) and pathological adrenals and to explore whether there are correlation between the expression of these proteins and the in vitro response to sirolimus. For this purpose, the MTOR, S6K1 (RPS6KB1), and 4EBP1 (EIF4EBP1) mRNA expression were evaluated in ten NAs, ten adrenal hyperplasias (AHs), 17 adrenocortical adenomas (ACAs), and 17 ACCs by qPCR, whereas total(t)/phospho(p)-MTOR, t/p-S6K, and t/p-4EBP1 protein expression were assessed in three NAs, three AHs, six ACAs, and 20 ACCs by immunohistochemistry. The effects of sirolimus on cell survival and/or cortisol secretion in 12 human primary cultures of adrenocortical tumors (ATs) were also evaluated. In NAs and AHs, layer-specific expression of evaluated proteins was observed. S6K1 mRNA levels were lower in ACCs compared with NAs, AHs, and ACAs (P<0.01). A subset of ATs presented a moderate to high staining of the evaluated proteins. Median t-S6K1 protein expression in ACCs was lower than that in ACAs (P<0.01). Moderate to high staining of p-S6K1 and/or p-4EBP1 was observed in most ATs. A subset of ACCs not having moderate to high staining had a higher Weiss score than others (P<0.029). In primary AT cultures, sirolimus significantly reduced cell survival or cortisol secretion only in sporadic cases. In conclusion, these data suggest the presence of an activated mTOR pathway in a subset of ATs and a possible response to sirolimus only in certain ACC cases.

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