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SIRT1 at the crossroads of AKT1 and ER? in malignant pleural mesothelioma cells.


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 ER?. We further demonstrate an inhibitory feedback loop by ER?, activated by the selective agonist KB9520, on this axis both in vitro and in vivo.Our data broaden the current knowledge of ER? and AKT isoform-specific functions that could be valuable in the design of novel and effective therapeutic strategies for MPM.

SUBMITTER: Pinton G 

PROVIDER: S-EPMC4924721 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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SIRT1 at the crossroads of AKT1 and ERβ in malignant pleural mesothelioma cells.

Pinton Giulia G   Zonca Sara S   Manente Arcangela G AG   Cavaletto Maria M   Borroni Ester E   Daga Antonio A   Jithesh Puthen V PV   Fennell Dean D   Nilsson Stefan S   Moro Laura L  

Oncotarget 20160301 12


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 SI  ...[more]

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