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

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.

Inhibition of lymphoma vascularization and dissemination by estrogen receptor β agonists

“…Inhibition of Granta-519 tumor growth was also seen following treatment with another highly selective ERb agonist, KB099520 (supplemental Figure 2). 5,26,27 Furthermore, the tumorinhibiting effect of DPN was abolished if DPN was coadministered with the ER antagonist ICI 182.780 or impaired when coadministered with estradiol (supplemental Figures 3 and 4a). Note that estradiol is only a weak partial agonist when it comes to inhibition of lymphoma growth in vivo (supplemental Figure 4b), 5 suggesting that the tumor-inhibiting effect indeed was ER-mediated.…”

Estrogen receptors alpha (ERα) and beta (ERβ): Subtype-selective ligands and clinical potential

“…Mice injected with cancer cells expressing endogenous ERβ and treated with KB9520 experienced a decrease in tumor size and again KB9520 treatment was not toxic. Interestingly, ERβ seems to interfere with the mitochondrial respiratory chain complex and mitochondrial ATP production in tumor cells [104]. …”

Malignant pleural mesothelioma and mesothelial hyperplasia: A new molecular tool for the differential diagnosis

“…The majority of the deregulated genes in MPM belong to the following pathways: angiogenesis, cell adhesion, p53 signalling, integrin signalling, MAPK signalling, apoptosis and cell cycle regulation [26–32]. Although there is a clear implication of these genes in cancer, sensitive markers for MPM are still missing.…”