Metabotropic glutamate receptor-1: a potential therapeutic target for the treatment of breast cancer.
Metabotropic glutamate receptor-1: a potential therapeutic target for the treatment of breast cancer.
复制标题
代谢性谷氨酸受体1：治疗乳腺癌的潜在治疗靶点。
DOI：
10.1007/s10549-011-1624-x
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发表时间：
2012-04
影响因子：
3.8
通讯作者：
Gorski, David H.
中科院分区：
文献类型：
--
作者：
Speyer, Cecilia L.;Smith, Jennifer S.;Banda, Malathi;DeVries, John A.;Mekani, Tassia;Gorski, David H.
代谢型谷氨酸受体是 G 蛋白偶联受体，通常在中枢神经系统中表达，介导神经元兴奋性、突触可塑性和神经递质释放的反馈抑制。然而，最近的数据表明，这些受体也在某些癌症中表达并发挥作用，尤其是黑色素瘤。我们检测了三阴性乳腺癌细胞中代谢型谷氨酸受体-1（基因：GRM1；蛋白质：mGluR1）的表达，并评估了其在调节这些细胞的促增殖表型中的作用。 mGluR1 抑制剂（利鲁唑或 BAY36-7620）以时间和剂量依赖性方式抑制三阴性乳腺癌细胞的增殖，并且这种抑制与细胞凋亡增加相关，如 PARP 裂解产物和膜联蛋白 V 染色的增加所证明的。与非沉默对照相比，使用表达靶向 GRM1 的 shRNA 的慢病毒构建体敲低 mGluR1 也抑制了增殖。此外，通过腹膜内注射利鲁唑或 BAY36-7620 治疗携带 MDA-MB-231 异种移植物的小鼠，肿瘤体积显着减少高达 80%。此外，利鲁唑对小鼠体内的三阴性乳腺癌异种移植物有效，其剂量相当于目前用于治疗人类肌萎缩侧索硬化症的剂量。我们的观察结果表明 mGluR1 和谷氨酸信号传导是治疗乳腺癌的一个有前途的新分子靶点。更有前景的是，利鲁唑是一种低毒性的口服药物，代表了治疗三阴性乳腺癌的一种有前途的方法。
Metabotropic glutamate receptors are G-protein-coupled receptors normally expressed in the central nervous system where they mediate neuronal excitability, synaptic plasticity, and feedback inhibition of neurotransmitter release. However, recent data suggest that these receptors are also expressed and functional in some cancers, most notably melanoma. We detected the expression of metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in triple negative breast cancer cells and evaluated its role in regulating the pro-proliferative phenotype of these cells. mGluR1 inhibitors (Riluzole or BAY36-7620) inhibited the proliferation of triple negative breast cancer cells in a time- and dose-dependent manner and this inhibition correlated with increased apoptosis as demonstrated by increase in PARP cleavage products and Annexin V staining. mGluR1 knockdown using Lentiviral constructs expressing shRNA targeting GRM1 also inhibited proliferation compared to non-silencing controls. In addition, treatment of mice bearing MDA-MB-231 xenografts with Riluzole or BAY36-7620, by intraperitoneal injection, resulted in a significant reduction in tumor volume of up to 80%. Moreover, Riluzole was effective against triple negative breast cancer xenografts in mice at doses equivalent to those currently being used in humans for the treatment of amyotrophic lateral sclerosis. Our observations implicate mGluR1 and glutamate signaling as a promising new molecular target for the treatment of breast cancer. Even more promising, Riluzole, because it is an oral drug that can be administered with low toxicity, represents a promising approach in the treatment of triple negative breast cancer.
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DOI：
10.1158/1078-0432.ccr-10-1276
发表时间：
2011-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Khan AJ;Wall B;Ahlawat S;Green C;Schiff D;Mehnert JM;Goydos JS;Chen S;Haffty BG
通讯作者：
Haffty BG
影响因子：
4.8
作者：
Marin, Yari E.;Namkoong, Jin;Chen, Suzie
通讯作者：
Chen, Suzie
影响因子：
30.8
作者：
Pollock, PM;Cohen-Solal, K;Chen, S
通讯作者：
Chen, S
影响因子：
11.2
作者：
Kuperwasser, C;Dessain, S;Rosenblatt, M
通讯作者：
Rosenblatt, M
影响因子：
6.1
作者：
Noh, KM;Hwang, JY;Koh, JY
通讯作者：
Koh, JY