title: Interferon-β is a potent inhibitor of cell growth and cortisol production in vitro and sensitizes human adrenocortical carcinoma cells to mitotane.
abstract: 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.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Koetsveld
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vitale
authors.forename: Richard A
authors.initials: RA
authors.lastname: Feelders
authors.forename: Marlijn
authors.initials: M
authors.lastname: Waaijers
authors.forename: Diana M
authors.initials: DM
authors.lastname: Sprij-Mooij
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.forename: Ernst-Jan M
authors.initials: EJ
authors.lastname: Speel
authors.forename: Johannes
authors.initials: J
authors.lastname: Hofland
authors.forename: Steven W J
authors.initials: SW
authors.lastname: Lamberts
authors.forename: Wouter W
authors.initials: WW
authors.lastname: de Herder
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000378:metabolism*; D018268:Adrenocortical Carcinoma / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D016899:Interferon-beta / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D008939:Mitotane / Q000008:administration & dosage*; D010750:Phosphoproteins / Q000235:genetics; D014407:Tumor Cells, Cultured; D055815:Young Adult; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D000970:Antineoplastic Agents; C035170:IGF2 protein, human; D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D007335:Insulin-Like Growth Factor II; D016899:Interferon-beta; D008939:Mitotane; D003577:Cytochrome P-450 Enzyme System; D006854:Hydrocortisone
keywords: adrenocortical carcinoma; insulin-like growth factor 2; interferon receptor; mitotane; type 1 interferons