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SIRT1 at the crossroads of AKT1 and ERβ in malignant pleural mesothelioma cells.
- Source :
-
Oncotarget [Oncotarget] 2016 Mar 22; Vol. 7 (12), pp. 14366-79. - Publication Year :
- 2016
-
Abstract
- In this report, we show that malignant pleural mesothelioma (MPM) patients whose tumors express high levels of AKT1 exhibit a significantly worse prognosis, whereas no significant correlation with AKT3 expression is observed. We provide data that establish a phosphorylation independent role of AKT1 in affecting MPM cell shape and anchorage independent cell growth in vitro and highlight the AKT1 isoform-specific nature of these effects.We describe that AKT1 activity is inhibited by the loss of SIRT1-mediated deacetylation and identify, by mass spectrometry, 11 unique proteins that interact with acetylated AKT1.Our data demonstrate a role of the AKT1/SIRT1/FOXM1 axis in the expression of the tumor suppressor ERβ. We further demonstrate an inhibitory feedback loop by ERβ, activated by the selective agonist KB9520, on this axis both in vitro and in vivo.Our data broaden the current knowledge of ERβ and AKT isoform-specific functions that could be valuable in the design of novel and effective therapeutic strategies for MPM.
- Subjects :
- Animals
Apoptosis drug effects
Cell Proliferation drug effects
Estrogen Receptor beta agonists
Estrogens pharmacology
Forkhead Box Protein M1 metabolism
Humans
Lung Neoplasms drug therapy
Lung Neoplasms metabolism
Male
Mesothelioma drug therapy
Mesothelioma metabolism
Mesothelioma, Malignant
Mice
Mice, Nude
Pleural Neoplasms drug therapy
Pleural Neoplasms metabolism
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Biomarkers, Tumor metabolism
Estrogen Receptor beta metabolism
Lung Neoplasms pathology
Mesothelioma pathology
Pleural Neoplasms pathology
Proto-Oncogene Proteins c-akt metabolism
Sirtuin 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 26885609
- Full Text :
- https://doi.org/10.18632/oncotarget.7321