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The role of mTOR inhibitors in the inhibition of growth and cortisol secretion in human adrenocortical carcinoma cells.
MedLine Citation:
PMID:  22420007     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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 evaluated mTOR, IGFII and IGFI-receptor expression; the effects of sirolimus and temsirolimus on cell growth; the effects of sirolimus on apoptosis, cellcycle and cortisol production. Moreover, the effects of sirolimus on basal- and IGFII-stimulated H295 cell-colony-growth and on basal- and IGFI-stimulated phospho-AKT, phospho-S6K1 and phospho-ERK in H295 and SW13 were studied. Finally, we evaluated the effects of combination treatment of sirolimus with an IGFII-neutralizing antibody. We found that H295 and HAC15 expressed IGFII 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 IGFII, suggesting the involvement of other autocrine regulators of mTOR-pathways. In H295, sirolimus activated escape-pathways. The blocking of endogenously produced IGFII 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 IGFII could have greater effects than mTOR-inhibitors alone.
Authors:
Maria Cristina De Martino; Peter M van Koetsveld; Richard A Feelders; Diana Sprij-Mooij; Marlijn M Waaijers; Steven Wj Lamberts; Wouter W de Herder; Annamaria Al Colao; Rosario Pivonello; Leo Hofland
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-14
Journal Detail:
Title:  Endocrine-related cancer     Volume:  -     ISSN:  1479-6821     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9436481     Medline TA:  Endocr Relat Cancer     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
M De Martino, Internal Medicine, Erasmus Medical Center, Rotterdam, 3015 GD, Netherlands.
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