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

Our plain-English summary of Estrogen receptor β activation impairs mitochondrial oxidative metabolism and affects malignant mesothelioma cell growth in vitro and in vivo, by A.G. Manente, D. Valenti, G. Pinton, et al (Oncogenesis, 2013).

The study

• Authors: 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
• Journal: Oncogenesis
• Published: 2013;2(9):e72
• Cited by: 37 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study of malignant pleural mesothelioma did not examine asbestos exposure. The authors analyzed two public gene-expression data sets covering 93 mesothelioma tumors. Tumors with high levels of the gene for estrogen receptor beta (ERβ) had lower levels of SDHB, a gene for part of the cell's energy machinery. Protein tests on 20 patient tissue samples supported this inverse pattern. In REN mesothelioma cells, switching off SDHB raised ERβ but did not change cell growth. Activating ERβ with the drugs KB9520 or DPN impaired two energy-producing complexes in mitochondria (complexes II and IV). Extra ERβ reduced mitochondrial energy (ATP) production. In cells, glycolysis-blocking drugs strengthened ERβ's effects. In mice given mesothelioma cells in the abdomen (7 per group), KB9520 did not reduce growth of tumors from ERβ-negative MSTO-211H cells. It did reduce REN tumor size compared with untreated controls, and tumor mass shrank in 2 of 7 treated mice after 20 days. The authors concluded that an ERβ agonist, alone or with glycolysis inhibitors, may be a future treatment strategy for ERβ-positive mesothelioma. They said the reason for the SDHB-ERβ pattern is still unknown.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: computer (in silico) meta-analysis of published tumor gene-expression data, protein analysis of patient tissue samples, cell-line experiments, and a mouse tumor experiment
• Who was studied: Gene-expression data from 93 malignant mesothelioma tumors in two public data sets (GSE 2549, 40 tumors; GSE 29354, 53 tumors) and 20 tissue samples from mesothelioma patients of different histological subtypes. The experiments used the epithelioid REN mesothelioma cell line, the biphasic MSTO-211H cell line, normal mesothelial MET5A cells, and six-week-old male CD1 nude mice (7 per group). Places and dates of patient sampling are not given.
• Exposure: Not asbestos. The study altered estrogen receptor beta (ERβ) levels by over-expression or silencing, and silenced the SDHB gene. ERβ was activated with the selective agonists KB9520 and DPN: 10 nM in cells, and 10 mg/kg body weight/day of KB9520 by daily injection under the skin in mice. Some cell experiments also used the glycolysis inhibitors 2-Deoxy-D-glucose and 3PO.
• Main results:
  • In tumors with high ESR2 (ERβ gene) expression, SDHB was among the genes with lower expression.
  • The inverse relationship between ESR2 and SDHB was supported by protein (western blot) analysis of patient tissue samples (20 samples).
  • In REN cells, silencing SDHB increased ESR2 gene activity and ERβ protein.
  • Short-term SDHB silencing in REN cells did not change cell growth compared with control cells.
  • Activating ERβ with KB9520 or DPN strongly impaired mitochondrial complex II and IV activity in REN cells, both control and SDHB-silenced.
  • In normal mesothelial MET5A cells, KB9520 and DPN did not severely impair complex II and IV activity, COX7AR expression or cell growth.
  • ERβ over-expression in REN cells reduced mitochondrial ATP production.
  • In cells, glycolysis inhibitors strengthened the effects of over-expressed or KB9520-activated ERβ.
  • In mice given ERβ-negative MSTO-211H cells, tumor growth was not reduced by KB9520.
  • In mice given ERβ-expressing REN cells, KB9520 reduced tumor size compared with vehicle-treated controls within 10 days of treatment.
  • In 2 of 7 KB9520-treated mice with REN tumors, initial tumor mass was reduced after 20 days. In the other 5 of 7, the tumor growth rate was slowed.
  • KB9520 was not toxic to the mice, as judged by body weight.
• The authors' conclusion: The authors concluded that treatment with an ERβ agonist, alone or combined with glycolysis inhibitors, may be a future strategy for managing ERβ-positive malignant mesothelioma and peritoneal mesothelioma.
• Limitations the authors state:
  • The authors stated that the reason SDHB and ERβ levels are inversely related, in patients and in REN cells, is still unknown.
  • The authors stated that the mechanism behind increased ERβ gene activity in KB9520-treated mouse tumors is not clear.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Meta-Analysis, Pleural Mesothelioma.

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