title: SIRT1 at the crossroads of AKT1 and ERβ 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 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Piemonte Orientale "A. Avogadro", 28100 Novara, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Pinton
authors.affiliation: Department of Pharmaceutical Sciences, University of Piemonte Orientale "A. Avogadro", 28100 Novara, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Zonca
authors.affiliation: Department of Pharmaceutical Sciences, University of Piemonte Orientale "A. Avogadro", 28100 Novara, Italy.
authors.forename: Arcangela G
authors.initials: AG
authors.lastname: Manente
authors.affiliation: Department of Sciences and Technological Innovation, University of Piemonte Orientale "A. Avogadro", 15121 Alessandria, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Cavaletto
authors.affiliation: Department of Health Sciences, University of Piemonte Orientale "A. Avogadro", 28100 Novara, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Borroni
authors.affiliation: Department of Integrated Oncological Therapies, IRCCS San Martino-IST, 16132 Genova, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Daga
authors.affiliation: Division of Biomedical Informatics Research, Sidra Medical and Research Center, 26999 Doha, Qatar.
authors.forename: Puthen V
authors.initials: PV
authors.lastname: Jithesh
authors.affiliation: Department of Cancer Studies, Cancer Research UK Leicester Centre, University of Leicester, LE1 7RH Leicester, UK.
authors.forename: Dean
authors.initials: D
authors.lastname: Fennell
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, S-141 57 Huddinge, Sweden.|Karo Bio AB, Novum, S-141 57 Huddinge, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Nilsson
authors.affiliation: Department of Pharmaceutical Sciences, University of Piemonte Orientale "A. Avogadro", 28100 Novara, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Moro
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D047629:Estrogen Receptor beta / Q000819:agonists / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D000072278:Forkhead Box Protein M1 / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D051379:Mice; D008819:Mice, Nude; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D047629:Estrogen Receptor beta; D004967:Estrogens; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: AKT1; SIRT1; estrogen receptor beta; malignant pleural mesothelioma