Activation of the Farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential
Activation of the Farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential
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DOI：
10.1016/j.canlet.2015.10.031
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发表时间：
2016-01-01
期刊：
影响因子：
9.7
通讯作者：
Plant, Nick J.
中科院分区：
文献类型：
--
作者：
Alasmael, Noura;Mohan, Rati;Plant, Nick J.
乳腺癌是女性中最常见的癌症形式，但成功的治疗受到乳腺肿瘤异质性的困扰：对乳腺癌敏感的肿瘤存在有效的治疗方法，但三阴性乳腺癌导致生存率低。越来越感兴趣的一个领域是代谢重编程，其中药物诱导的肿瘤代谢景观的改变减缓肿瘤生长和/或增加对现有治疗的敏感性。核受体是代谢和转运蛋白表达的核心转录因子，因此代表了代谢重编程的潜在靶点。我们发现，通过其内源性配体CDCA或合成的GW 4064激活核受体FXR，导致具有不同表型的四种乳腺癌细胞系的细胞死亡：MCF-10A（正常），MCF-7（受体阳性），MDA-MB-231和MDA-MB-468（三阴性）。此外，我们表明，细胞死亡的机制主要是通过内在的凋亡途径。最后，我们证明了FXR激动剂不会刺激乳腺癌细胞系的迁移，这是一种重要的潜在不良反应。总之，我们的数据支持继续检查FXR激动剂作为一类新的治疗乳腺癌的疗法。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Breast cancer is the commonest form of cancer in women, but successful treatment is confounded by the heterogeneous nature of breast tumours: Effective treatments exist for hormone-sensitive tumours, but triple-negative breast cancer results in poor survival. An area of increasing interest is metabolic reprogramming, whereby drug-induced alterations in the metabolic landscape of a tumour slow tumour growth and/or increase sensitivity to existing therapeutics. Nuclear receptors are transcription factors central to the expression of metabolic and transport proteins, and thus represent potential targets for metabolic reprogramming. We show that activation of the nuclear receptor FXR, either by its endogenous ligand CDCA or the synthetic GW4064, leads to cell death in four breast cancer cell lines with distinct phenotypes: MCF-10A (normal), MCF-7 (receptor positive), MDA-MB-231 and MDA-MB-468 (triple negative). Furthermore, we show that the mechanism of cell death is predominantly through the intrinsic apoptotic pathway. Finally, we demonstrate that FXR agonists do not stimulate migration in breast cancer cell lines, an important potential adverse effect. Together, our data support the continued examination of FXR agonists as a novel class of therapeutics for the treatment of breast cancer. (C) 2015 Elsevier Ireland Ltd. All rights reserved.