Oncotarget

Research Papers:

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 and Laura Moro

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Oncotarget. 2016; 7:14366-14379. https://doi.org/10.18632/oncotarget.7321

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Abstract

Giulia Pinton1, Sara Zonca1, Arcangela G. Manente1, Maria Cavaletto2, Ester Borroni3, Antonio Daga4, Puthen V. Jithesh5, Dean Fennell6, Stefan Nilsson7,8, Laura Moro1

1Department of Pharmaceutical Sciences, University of Piemonte Orientale “A. Avogadro”, 28100 Novara, Italy

2Department of Sciences and Technological Innovation, University of Piemonte Orientale “A. Avogadro”, 15121 Alessandria, Italy

3Department of Health Sciences, University of Piemonte Orientale “A. Avogadro”, 28100 Novara, Italy

4Department of Integrated Oncological Therapies, IRCCS San Martino-IST, 16132 Genova, Italy

5Division of Biomedical Informatics Research, Sidra Medical and Research Center, 26999 Doha, Qatar

6Department of Cancer Studies, Cancer Research UK Leicester Centre, University of Leicester, LE1 7RH Leicester, UK

7Department of Biosciences and Nutrition, Karolinska Institutet, S-141 57 Huddinge, Sweden

8Karo Bio AB, Novum, S-141 57 Huddinge, Sweden

Correspondence to:

Laura Moro, e-mail: [email protected]

Keywords: malignant pleural mesothelioma, AKT1, SIRT1, estrogen receptor beta

Received: November 03, 2015    Accepted: January 29, 2016    Published: February 11, 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.


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