Document Detail


The rapamycin-derivative RAD001 (everolimus) inhibits cell viability and interacts with the Akt-mTOR-p70S6K pathway in human medullary thyroid carcinoma cells.
MedLine Citation:
PMID:  19815051     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Over-expression of the proto-oncogene Akt/PKB has been demonstrated in some neuroendocrine tumor models. Akt may activate downstream proteins such as mTOR and p70S6K, inducing tumor proliferation. The rapamycin-derivative RAD001, everolimus, interacts with this pathway by antagonizing mTOR, but its effects on neuroendocrine tumors are largely unknown. We explored the mechanism of action of RAD001 on cell proliferation, hormonal secretion and on Akt/mTOR/p70S6K pathway activation, in a human medullary thyroid carcinoma (MTC) cell-line (TT) and in cells derived from human MTCs. Treatment with RAD001 significantly inhibited cell viability in a dose- and time-dependent fashion, and diminished phosphorylation of Akt downstream targets, mTOR and p70S6K, in both TT cell-line and cultured human MTCs. Akt phosphorylation was not affected by RAD001. RAD001 induced cell-cycle arrest in the G(0)/G(1) phase in TT cells, but had no effect on apoptosis. Moreover, RAD001 did not affect calcitonin and carcinoembryonic antigen secretion in TT cells and in human MTCs. RAD001 seems to have potent anti-proliferative effect in human MTC cells, which suggest that clinical trials of this agent are of considerable interest.
Authors:
Simona Grozinsky-Glasberg; Hadara Rubinfeld; Yardena Nordenberg; Alexander Gorshtein; Michal Praiss; Efrat Kendler; Rafael Feinmesser; Ashley B Grossman; Ilan Shimon
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-10-06
Journal Detail:
Title:  Molecular and cellular endocrinology     Volume:  315     ISSN:  1872-8057     ISO Abbreviation:  Mol. Cell. Endocrinol.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-02-01     Completed Date:  2010-07-05     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7500844     Medline TA:  Mol Cell Endocrinol     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  87-94     Citation Subset:  IM    
Copyright Information:
2009 Elsevier Ireland Ltd. All rights reserved.
Affiliation:
Institute of Endocrinology, Beilinson Hospital, Rabin Medical Center, Petah Tiqva, Israel. simonag@clalit.org.il
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MeSH Terms
Descriptor/Qualifier:
Aged
Calcitonin / metabolism
Carcinoembryonic Antigen / metabolism
Cell Cycle / drug effects
Cell Survival / drug effects*
Humans
Immunosuppressive Agents / pharmacology*
Intracellular Signaling Peptides and Proteins / genetics,  metabolism*
Male
Middle Aged
Phosphorylation
Protein-Serine-Threonine Kinases / genetics,  metabolism*
Proto-Oncogene Proteins c-akt / genetics,  metabolism*
Ribosomal Protein S6 Kinases, 70-kDa / genetics,  metabolism*
Signal Transduction / drug effects*,  physiology
Sirolimus / analogs & derivatives*,  pharmacology
Thyroid Gland / anatomy & histology,  pathology
Thyroid Neoplasms / metabolism*,  pathology,  physiopathology
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Carcinoembryonic Antigen; 0/Immunosuppressive Agents; 0/Intracellular Signaling Peptides and Proteins; 159351-69-6/everolimus; 53123-88-9/Sirolimus; 9007-12-9/Calcitonin; EC 2.7.1.-/mTOR protein; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/Ribosomal Protein S6 Kinases, 70-kDa

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