Estrogen receptor β activation impairs mitochondrial oxidative metabolism and affects malignant mesothelioma cell growth in vitro and in vivo

Manente, A. G., Valenti, D., Pinton, G., Jithesh, P. V., Daga, A., Rossi, L., Gray, S. G., O'Byrne, Ken J., Fennell, D. A., Vacca, R. A., Nilsson, S., Mutti, L., & Moro, L. (2013) Estrogen receptor β activation impairs mitochondrial oxidative metabolism and affects malignant mesothelioma cell growth in vitro and in vivo. Oncogenesis, 2(e72).

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Estrogen receptor (ER)-β has been shown to possess a tumor suppressive effect, and is a potential target for cancer therapy. Using gene-expression meta-analysis of human malignant pleural mesothelioma, we identified an ESR2 (ERβ coding gene) signature. High ESR2 expression was strongly associated with low succinate dehydrogenase B (SDHB) (which encodes a mitochondrial respiratory chain complex II subunit) expression. We demonstrate that SDHB loss induced ESR2 expression, and that activated ERβ, by over-expression or by selective agonist stimulation, negatively affected oxidative phosphorylation compromising mitochondrial complex II and IV activity. This resulted in reduced mitochondrial ATP production, increased glycolysis dependence and impaired cell proliferation. The observed in vitro effects were phenocopied in vivo using a selective ERβ agonist in a mesothelioma mouse model. On the whole, our data highlight an unforeseen interaction between ERβ-mediated tumor suppression and energy metabolism that may be exploited to improve on the therapy for clinical management of malignant mesothelioma.

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ID Code: 67775
Item Type: Journal Article
Refereed: Yes
Keywords: adenosine triphosphate, cytochrome c oxidase, estrogen receptor beta, succinate dehydrogenase, succinate dehydrogenase (ubiquinone), succinate dehydrogenase b, unclassified drug, aerobic metabolism, animal experiment, animal model, article, cancer growth, cancer inhibition, cell proliferation, cell viability, controlled study, energy metabolism, enzyme activity, gene expression, gene identification, glycolysis, human, human cell, in vitro study, in vivo study, metabolic regulation, mitochondrial respiration, mouse, nonhuman, oxidative phosphorylation, pleura mesothelioma, priority journal
DOI: 10.1038/oncsis.2013.32
ISSN: 21579024
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2013 Macmillan Publishers Limited
Copyright Statement: Oncogenesis is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit
Deposited On: 24 Feb 2014 23:18
Last Modified: 25 Feb 2014 23:04

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