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

Giulia Pinton, Sara Zonca, Arcangela G. Manente, Maria Cavaletto, Ester Borroni, Antonio Daga, Puthen V. Jithesh, Dean Fennell, Stefan Nilsson, Laura Moro

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8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)14366-14379
Number of pages14
JournalOncotarget
Volume7
Issue number12
DOIs
Publication statusPublished - 22 Mar 2016

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Keywords

  • AKT1
  • Estrogen receptor beta
  • Malignant pleural mesothelioma
  • SIRT1

ASJC Scopus subject areas

  • Oncology

Cite this

Pinton, G., Zonca, S., Manente, A. G., Cavaletto, M., Borroni, E., Daga, A., Jithesh, P. V., Fennell, D., Nilsson, S., & Moro, L. (2016). SIRT1 at the crossroads of AKT1 and ERβ in malignant pleural mesothelioma cells. Oncotarget, 7(12), 14366-14379. https://doi.org/10.18632/oncotarget.7321