Intracellular lactate-mediated induction of estrogen receptor beta (ERβ) in biphasic malignant pleural mesothelioma cells
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Arcangela G. Manente1,*, Giulia Pinton1,*, Sara Zonca1, Michele Cilli2, Maurizio Rinaldi1, Antonio Daga2, Stefan Nilsson3,4, Laura Moro1
1Department of Pharmaceutical Sciences, University of Piemonte Orientale “A. Avogadro”, 28100, Novara, Italy
2IRCCS San Martino-IST, 16132, Genova, Italy
3Karo Bio AB, Novum, S-141 57, Huddinge, Sweden
4Department of Biosciences and Nutrition, Karolinska Institutet, Novum, S-141 57, Huddinge, Sweden
*These authors have contributed equally to this work
Laura Moro, e-mail: [email protected]
Keywords: biphasic pleural mesothelioma, lactate, estrogen receptor beta, targeted therapy
Received: March 16, 2015 Accepted: June 26, 2015 Published: July 09, 2015
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.
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