Intracellular lactate-mediated induction of estrogen receptor beta (ERβ) in biphasic malignant pleural mesothelioma cells
Intracellular lactate-mediated induction of estrogen receptor beta (ERβ) in biphasic malignant pleural mesothelioma cells
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DOI：
10.18632/oncotarget.4486
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发表时间：
2015-09-22
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影响因子：
--
通讯作者：
Moro, Laura
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作者：
Manente, Arcangela G.;Pinton, Giulia;Moro, Laura
双相恶性胸膜间皮瘤（MPM）是第二个最常见的组织型的MPM。它的组织学特征是上皮样和肉瘤样特征的同时存在，后者与较差的预后相关。在这份报告中，我们描述了沉默AKT 1在梭形双相MPM细胞促进向上皮样表型的转变。此外，AKT 1沉默导致乳酸/H+同向转运体MCT 4及其伴侣CD 147/Basigin的表达降低，并诱导雌激素受体β（ER β）表达。我们提供的证据表明，ER β表达是由细胞内乳酸浓度增加诱导的。ER β阴性双相MPM在裸鼠中的球体培养和肿瘤生长导致ER β表达的诱导和对选择性激动剂KB 9520的反应。在这两种模型中，用ER β激动剂处理导致细胞增殖减少、MCT 4和CD 147/Basigin表达减少以及AKT 1乙酰化和失活增加。总的来说，响应于代谢变化，ER β表达被诱导，并通过选择性激动剂活化发挥抗肿瘤作用。通过选择性激动剂靶向ER β逆转更具侵袭性的双相间皮瘤组织型的可能性可能代表了一种新的有效治疗策略。
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 beta (ER beta) expression. We provide evidence that ER beta expression is induced by increased intracellular lactate concentration. Spheroid culturing and tumor growth of ER beta negative biphasic MPM in nude mice resulted in the induction of ER beta expression and response to the selective agonist KB9520. In both models, the treatment with the ER beta 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, ER beta 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 ER beta with a selective agonist could represent a new effective treatment strategy.