title: The role of mTOR inhibitors in the inhibition of growth and cortisol secretion in human adrenocortical carcinoma cells.
abstract: 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.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Room Ee530b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: De Martino
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Koetsveld
authors.forename: Richard A
authors.initials: RA
authors.lastname: Feelders
authors.forename: Diana
authors.initials: D
authors.lastname: Sprij-Mooij
authors.forename: Marlijn
authors.initials: M
authors.lastname: Waaijers
authors.forename: Steven W J
authors.initials: SW
authors.lastname: Lamberts
authors.forename: Wouter W
authors.initials: WW
authors.lastname: de Herder
authors.forename: Annamaria
authors.initials: A
authors.lastname: Colao
authors.forename: Rosario
authors.initials: R
authors.lastname: Pivonello
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; C035170:IGF2 protein, human; D047428:Protein Kinase Inhibitors; C401859:temsirolimus; D007335:Insulin-Like Growth Factor II; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D006854:Hydrocortisone