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Potent Inhibitory Effects of Type I Interferons on Human Adrenocortical Carcinoma Cell Growth

Departments of Internal Medicine (P.M.v.K., G.V., W.W.d.H., R.A.F., K.v.d.W., M.W., A.-J.v.d.L., S.W.J.L., L.J.H.) and Surgery (C.H.J.v.E), Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands; Department of Molecular Cell Biology (E.-J.M.S.), Research Institute for Growth and Development, University of Maastricht, NL-6200 MD Maastricht, The Netherlands; and Department of Immunology (E.C.), Berlex Bioscience Inc., Richmond, California 94006

Address all correspondence and requests for reprints to: Leo J. Hofland, Department of Internal Medicine, Erasmus Medical Center, Room Ee53ob, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail: l.hofland{at}erasmusmc.nl.

Context: Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Despite efforts to develop new therapeutic regimens for metastatic ACC, surgery remains the mainstay of treatment. Interferons are known to exert tumor-suppressive effects in several types of human cancer.

Design: We evaluated the tumor-suppressive effects of type I interferons (IFN)-2b and IFNß on the H295 and SW13 human ACC cell lines.

Results: As determined by quantitative RT-PCR analysis and immunocytochemistry, H295 and SW13 cells expressed the active type I IFN receptor (IFNAR) mRNA and protein (IFNAR-1 and IFNAR-2c subunits). Both IFN2b and IFNß1a significantly inhibited ACC cell growth in a dose-dependent manner, but the effect of IFNß1a (IC₅₀ 5 IU/ml, maximal inhibition 96% in H295; IC₅₀ 18 IU/ml, maximal inhibition 85% in SW13) was significantly more potent, compared with that of IFN2b (IC₅₀ 57 IU/ml, maximal inhibition 35% in H295; IC₅₀ 221 IU/ml, maximal inhibition 60% in SW13). Whereas in H295 cells both IFNs induced apoptosis and accumulation of the cells in S phase, the antitumor mechanism in SW13 cells involved cell cycle arrest only. Inhibitors of caspase-3, caspase-8, and caspase-9 counteracted the apoptosis-inducing effect by IFNß1a in H295 cells. In H295 cells, IFNß1a, but not IFN2b, also strongly suppressed the IGF-II mRNA expression, an important growth factor and hallmark in ACC.

Conclusions: IFNß1a is much more potent than IFN2b to suppress ACC cell proliferation in vitro by induction of apoptosis and cell cycle arrest. Further studies are required to evaluate the potency of IFNß1a to inhibit tumor growth in vivo.