Intracellular lactate-mediated induction of estrogen receptor beta (ERβ) in biphasic malignant pleural mesothelioma cells

Our plain-English summary of Intracellular lactate-mediated induction of estrogen receptor beta (ERβ) in biphasic malignant pleural mesothelioma cells, by A.G. Manente, G. Pinton, S. Zonca, et al (Oncotarget, 2015).

The study

• Authors: A.G. Manente, G. Pinton, S. Zonca, M. Cilli, M. Rinaldi, A. Daga, S. Nilsson, L. Moro
• Journal: Oncotarget
• Published: 2015;6(28):25121-34
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This laboratory study used cultured cells and mice. It did not study asbestos exposure. The authors worked mainly with MSTO-211H, a cell line originally derived from a patient with biphasic malignant pleural mesothelioma. These cells normally lack estrogen receptor beta (ERβ). The authors also used the epithelioid REN cell line. Switching off the AKT1 gene in MSTO-211H cells raised lactate inside the cells, made them look more epithelioid and induced ERβ. Adding extra AKT1 to REN cells made them more spindle-like and lowered ERβ. Raising lactate inside MSTO-211H cells by other means also induced ERβ. These means were blocking the lactate exporter MCT4 (which raised lactate more than five times), adding 30 mM lactate, and growing the cells in low oxygen. The ERβ-activating drug KB9520 reduced the growth of cells grown in low oxygen and of cell clusters grown as spheroids. Mice were injected in the abdomen with MSTO-211H cells (8 per group). From 10 days of treatment, those given KB9520 had less tumor growth than mice given only the drug-free vehicle. The authors concluded that metabolic changes can promote ERβ expression in these cells and that a selective activating drug maintains its tumor-suppressing function.

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 using human mesothelioma cell lines (standard cultures and 3-dimensional spheroids) and a mouse tumor model
• Who was studied: Biphasic MSTO-211H and epithelioid REN malignant pleural mesothelioma cell lines. Six-week-old male CD1 nude mice were injected into the abdomen (intraperitoneally) with MSTO-211H cells, in 2 groups of 8 animals (the methods section elsewhere says ten).
• Exposure: No asbestos exposure was studied. The experimental treatments were:
• silencing AKT1 in MSTO-211H cells or overexpressing it in REN cells
• silencing the lactate transporter genes SLC16A3 (MCT4) and SLC16A1 (MCT1)
• 30 mM lactate
• low-oxygen (hypoxic) culture
• the selective ERβ agonist KB9520 (10 nM in cells; 10 mg/kg/day by injection under the skin in mice, days 15 to 40)
• Main results:
  • In MSTO-211H cells, AKT1 silencing increased intracellular lactate and shifted the cells toward an epithelioid appearance.
  • ERβ was significantly induced in AKT1-silenced MSTO-211H cells and significantly inhibited in REN cells overexpressing AKT1.
  • Silencing SLC16A3 (the lactate exporter MCT4) in MSTO-211H cells raised intracellular lactate more than five times. This was followed by induction of ERβ.
  • Treating MSTO-211H cells with 30 mM lactate increased intracellular lactate and induced ERβ.
  • In MSTO-211H cells grown in low oxygen, silencing the lactate importer gene SLC16A1 decreased intracellular lactate and decreased ERβ expression.
  • KB9520 significantly reduced the growth of MSTO-211H cells grown in low oxygen.
  • In MSTO-211H spheroids, ERβ appeared temporarily between days 3 and 5. It lasted until day 9 only in spheroids treated with KB9520.
  • Nine days of KB9520 treatment significantly inhibited spheroid growth.
  • From 10 days of treatment onward, mice treated with KB9520 had reduced tumor growth compared with vehicle-treated mice.
  • Tumors from KB9520-treated mice had increased ERβ expression compared with tumors from vehicle-treated mice.
  • Tumors from KB9520-treated mice had significantly lower phosphorylated (active) AKT than tumors from vehicle-treated mice.
• The authors' conclusion: The authors concluded that metabolic changes can promote ERβ expression in ER-negative cells, and that activation by a selective agonist maintains its expression and tumor-suppressive function.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Biphasic Mesothelioma, Pleural Mesothelioma, Epithelioid, Sarcomatoid, Prognosis.

Related studies

• Agonist activation of estrogen receptor beta (ERβ) sensitizes malignant pleural mesothelioma cells to cisplatin cytotoxicity — G. Pinton, A.G. Manente, et al. (2014)
• SIRT1 at the crossroads of AKT1 and ERβ in malignant pleural mesothelioma cells — G. Pinton, S. Zonca, et al. (2016)
• Estrogen receptor β exerts tumor repressive functions in human malignant pleural mesothelioma via EGFR inactivation and affects response to gefitinib — G. Pinton, W. Thomas, et al. (2010)
• KDM6B histone demethylase is an epigenetic regulator of estrogen receptor β expression in human pleural mesothelioma — A.G. Manente, G. Pinton, et al. (2016)
• Estrogen receptor-beta affects the prognosis of human malignant mesothelioma — G. Pinton, E. Brunelli, et al. (2009)
• Expression patterns of estrogen and androgen receptors in NSCLC patients according to the PD-L1 profile — V. Rodriguez-Lara, G. Cortés-Ramírez, et al. (2025)

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