The role of metabotropic glutamate receptor 5 on the stromal cell-derived factor-1/CXCR4 system in oral cancer.
The role of metabotropic glutamate receptor 5 on the stromal cell-derived factor-1/CXCR4 system in oral cancer.
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DOI：
10.1371/journal.pone.0080773
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Miyamoto Y
中科院分区：
文献类型：
--
作者：
Kuribayashi N;Uchida D;Kinouchi M;Takamaru N;Tamatani T;Nagai H;Miyamoto Y
我们已经证明，阻断CXCR 4可能是CXCR 4相关口腔癌的有效抗转移疗法。然而，由于CXCR 4拮抗剂目前在临床上用于诱导造血干细胞的动员，因此作为转移抑制剂连续给药可能导致持续性白细胞增多。在这项研究中，我们使用B88-SDF-1细胞研究了SDF-1/CXCR 4系统的新型治疗下游靶点，B88-SDF-1细胞具有自分泌SDF-1/CXCR 4系统，并在体内表现出远处转移的潜力。微阵列分析显示，418个基因在B88-SDF-1细胞中上调。我们鉴定了在B88-SDF-1细胞中高度上调的基因，代谢型谷氨酸受体5（mGluR 5），其在用CXCR 4拮抗剂1，1 ' -[1，4-亚苯基双（亚甲基）]双-1，4，8，1,1-四氮杂环十四烷八盐酸盐（AMD 3100）处理后下调。SDF-1/CXCR 4系统中mGluR 5 mRNA的上调主要由Ras-细胞外信号调节激酶（ERK）1/2途径调节。此外，B88-SDF-1细胞的生长不受mGluR 5激动剂（S）-3，5-DHPG（DHPG）或mGluR 5拮抗剂2-甲基-6-（苯乙炔基）吡啶（MPEP）和3-（（2-甲基-1，3-噻唑-4-基）乙炔基）吡啶（MTEP）的影响。然而，我们观察到DHPG促进B88-SDF-1细胞迁移，而MPEP和MTEP抑制B88-SDF-1细胞迁移。为了评估药物毒性，将拮抗剂腹膜内注射到免疫活性小鼠中4周。注射MPEP（5 mg/kg）和MTEP（5 mg/kg）的小鼠未表现出任何副作用，如血液毒性、过敏反应或体重减轻。拮抗剂的施用显著抑制B88-SDF-1细胞向裸鼠肺的转移。这些结果表明，用拮抗剂如MPEP和MTEP阻断mGluR 5可以防止CXCR 4相关口腔癌的转移，而不会引起副作用。
We have demonstrated that blocking CXCR4 may be a potent anti-metastatic therapy for CXCR4-related oral cancer. However, as CXCR4 antagonists are currently in clinical use to induce the mobilization of hematopoietic stem cells, continuous administration as an inhibitor for the metastasis may lead to persistent leukocytosis. In this study, we investigated the novel therapeutic downstream target(s) of the SDF-1/CXCR4 system, using B88-SDF-1 cells, which have an autocrine SDF-1/CXCR4 system and exhibit distant metastatic potential in vivo. Microarray analysis revealed that 418 genes were upregulated in B88-SDF-1 cells. We identified a gene that is highly upregulated in B88-SDF-1 cells, metabotropic glutamate receptor 5 (mGluR5), which was downregulated following treatment with 1,1’ -[1,4-Phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD3100), a CXCR4 antagonist. The upregulation of mGluR5 mRNA in the SDF-1/CXCR4 system was predominately regulated by the Ras-extracellular signal-regulated kinase (ERK)1/2 pathway. Additionally, the growth of B88-SDF-1 cells was not affected by the mGluR5 agonist (S)-3,5-DHPG (DHPG) or the mGluR5 antagonists 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP). However, we observed that DHPG promoted B88-SDF-1 cell migration, whereas both MPEP and MTEP inhibited B88-SDF-1 cell migration. To assess drug toxicity, the antagonists were intraperitoneally injected into immunocompetent mice for 4 weeks. Mice injected with MPEP (5 mg/kg) and MTEP (5 mg/kg) did not exhibit any side effects, such as hematotoxicity, allergic reactions or weight loss. The administration of antagonists significantly inhibited the metastasis of B88-SDF-1 cells to the lungs of nude mice. These results suggest that blocking mGluR5 with antagonists such as MPEP and MTEP could prevent metastasis in CXCR4-related oral cancer without causing side effects.
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DOI：
10.3390/molecules16032097
发表时间：
2011-03-02
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Cleva RM;Olive MF
通讯作者：
Olive MF
影响因子：
120.1
作者：
De Clercq, E
通讯作者：
De Clercq, E
影响因子：
4.8
作者：
Corti, C;Clarkson, RWE;Ferraguti, F
通讯作者：
Ferraguti, F
DOI：
10.1196/annals.1441.015
发表时间：
2008-01-01
期刊：
ADDICTION REVIEWS 2008
影响因子：
--
作者：
Carroll, F. Ivy
通讯作者：
Carroll, F. Ivy
影响因子：
3.8
作者：
Bathe, Oliver F.;Shaykhutdinov, Rustem;Vogel, Hans J.
通讯作者：
Vogel, Hans J.