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

A. G. Manente, D. Valenti, G. Pinton, P. V. Jithesh, A. Daga, L. Rossi, S. G. Gray, K. J. O'Byrne, D. A. Fennell, R. A. Vacca, S. Nilsson, L. Mutti, L. Moro

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article numbere72
JournalOncogenesis
Volume2
DOIs
Publication statusPublished - 2013

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Estrogen Receptors
Succinate Dehydrogenase
Growth
Neoplasms
Oxidative Phosphorylation
Mesothelioma
Glycolysis
Electron Transport
Energy Metabolism
Meta-Analysis
Estrogens
Adenosine Triphosphate
Cell Proliferation
Gene Expression
In Vitro Techniques
Malignant Mesothelioma
Therapeutics
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

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, K. J.; Fennell, D. A.; Vacca, R. A.; Nilsson, S.; Mutti, L.; Moro, L.

In: Oncogenesis, Vol. 2, e72, 2013.

Research output: Contribution to journalArticle

Manente, AG, Valenti, D, Pinton, G, Jithesh, PV, Daga, A, Rossi, L, Gray, SG, O'Byrne, KJ, Fennell, DA, Vacca, RA, 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, vol. 2, e72. https://doi.org/10.1038/oncsis.2013.32
Manente, A. G. ; Valenti, D. ; Pinton, G. ; Jithesh, P. V. ; Daga, A. ; Rossi, L. ; Gray, S. G. ; O'Byrne, K. J. ; Fennell, D. A. ; Vacca, R. A. ; Nilsson, S. ; Mutti, L. ; Moro, L. / Estrogen receptor β activation impairs mitochondrial oxidative metabolism and affects malignant mesothelioma cell growth in vitro and in vivo. In: Oncogenesis. 2013 ; Vol. 2.
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AU - Gray, S. G.

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