title: Intracellular lactate-mediated induction of estrogen receptor beta (ERβ) in biphasic malignant pleural mesothelioma cells.
abstract: Biphasic malignant pleural mesothelioma (MPM) is the second most common histotype of MPM. It is histologically characterized by the concomitant presence of epithelioid and sarcomatoid features, the latter associated with worse prognosis. In this report we describe that silencing of AKT1 in spindle-shaped biphasic MPM cells promotes the shift toward an epithelioid phenotype. Furthermore, AKT1 silencing resulted in decreased expression of the lactate/H+ symporter MCT4 and its chaperone CD147/Basigin, and in the induction of estrogen receptor β (ERβ) expression. We provide evidence that ERβ expression is induced by increased intracellular lactate concentration. Spheroid culturing and tumor growth of ERβ negative biphasic MPM in nude mice resulted in the induction of ERβ expression and response to the selective agonist KB9520. In both models, the treatment with the ERβ agonist results in reduced cell proliferation, decreased expression of MCT4 and CD147/Basigin and increased acetylation and inactivation of AKT1. Collectively, in response to metabolic changes, ERβ expression is induced and exerts an anti-tumor effect through selective agonist activation. The possibility to reverse the more aggressive biphasic mesothelioma histotype by targeting ERβ with a selective agonist could represent a new effective treatment strategy.
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 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: IRCCS San Martino-IST, 16132, Genova, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Cilli
authors.affiliation: Department of Pharmaceutical Sciences, University of Piemonte Orientale "A. Avogadro", 28100, Novara, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Rinaldi
authors.affiliation: IRCCS San Martino-IST, 16132, Genova, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Daga
authors.affiliation: Karo Bio AB, Novum, S-141 57, Huddinge, Sweden.|Department of Biosciences and Nutrition, Karolinska Institutet, 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; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D051926:Basigin / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047629:Estrogen Receptor beta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008819:Mice, Nude; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D018874:Spheroids, Cellular; D014162:Transfection; D047368:Tumor Burden; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; C497886:BSG protein, human; C000600034:ESR2 protein, human; D047629:Estrogen Receptor beta; D004967:Estrogens; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; C406962:SLC16A4 protein, human; D051926:Basigin; D019344:Lactic Acid; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: biphasic pleural mesothelioma; estrogen receptor beta; lactate; targeted therapy