Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
Biochimie. 2012 Nov;94(11):2366-75. doi: 10.1016/j.biochi.2012.06.006. Epub 2012 Jun 15.
Metabotropic glutamate receptors (mGlus) are G-protein-coupled receptors playing an important role in the central nervous system (CNS). Recently, mGlus have been identified in peripheral tissues, and aberrant expression or inhibition of the receptors functions in the development of certain cancers. However, the correlation of mGlu activity with hepatocellular carcinoma (HCC) remains unknown. In this study, we analyzed the effects of inhibiting mGlu5 activity in hepatocarcinoma cell lines and a xenograft model. Inactivation of mGlu5 with 2-Methyl-6-(phenylethyl)-pyridine (MPEP), a specific antagonist of the receptor, caused inhibition of cell growth, migration, and invasion of HepG2 and Bel-7402 cells, assessed by MTT assay, ATP production, wound healing, and Boyden chamber assay, respectively. Moreover, inhibition of tumor growth and the potential metastasis of hepatocellular carcinoma were also found in nude mice. Furthermore, mGlu5-mediated extracellular signal-regulated kinase (ERK) phosphorylation has been found to be partially involved in cell growth and migration, as detected by stimulation of (S)-3,5-Dihydroxyphenylglycine (DHPG), an agonist of the receptor, and blockage of MPEP and U0126, an inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (MEK). These data indicate that inhibiting the activity of mGlu5 has the molecular potential to suppress oncogenic actions by blocking downstream effector molecules. The study suggests that mGlu5 activity may contribute to understanding the development of HCC.
代谢型谷氨酸受体（mGluRs）是 G 蛋白偶联受体，在中枢神经系统（CNS）中发挥重要作用。最近，mGluRs 在周围组织中被鉴定出来，受体的异常表达或功能抑制与某些癌症的发展有关。然而，mGlu 活性与肝细胞癌（HCC）之间的相关性尚不清楚。在这项研究中，我们分析了抑制肝癌细胞系和异种移植模型中 mGlu5 活性的影响。用 2-甲基-6-（苯乙基）-吡啶（MPEP）使 mGlu5 失活，MPEP 是该受体的特异性拮抗剂，通过 MTT 测定、ATP 产生、划痕愈合和 Boyden 室测定分别评估，可抑制 HepG2 和 Bel-7402 细胞的细胞生长、迁移和侵袭。此外，还发现 MPEP 和丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（MEK）抑制剂 U0126 阻断 mGlu5 介导的细胞外信号调节激酶（ERK）磷酸化，部分参与细胞生长和迁移，在裸鼠中也发现抑制肝癌生长和潜在转移。这些数据表明，抑制 mGlu5 的活性具有通过阻断下游效应分子抑制致癌作用的分子潜力。该研究表明，mGlu5 活性可能有助于理解 HCC 的发展。
