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

// Giulia Pinton 1 , Sara Zonca 1 , Arcangela G. Manente 1 , Maria Cavaletto 2 , Ester Borroni 3 , Antonio Daga 4 , Puthen V. Jithesh 5 , Dean Fennell 6 , Stefan Nilsson 7, 8 , Laura Moro 1 1 Department of Pharmaceutical Sciences, University of Piemonte Orientale “A. Avogadro”, 28100 Novara, Italy 2 Department of Sciences and Technological Innovation, University of Piemonte Orientale “A. Avogadro”, 15121 Alessandria, Italy 3 Department of Health Sciences, University of Piemonte Orientale “A. Avogadro”, 28100 Novara, Italy 4 Department of Integrated Oncological Therapies, IRCCS San Martino-IST, 16132 Genova, Italy 5 Division of Biomedical Informatics Research, Sidra Medical and Research Center, 26999 Doha, Qatar 6 Department of Cancer Studies, Cancer Research UK Leicester Centre, University of Leicester, LE1 7RH Leicester, UK 7 Department of Biosciences and Nutrition, Karolinska Institutet, S-141 57 Huddinge, Sweden 8 Karo Bio AB, Novum, S-141 57 Huddinge, Sweden Correspondence to: Laura Moro, e-mail: laura.moro@uniupo.it 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.