Journal
BIOCHIMIE
Volume 94, Issue 11, Pages 2366-2375Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biochi.2012.06.006
Keywords
Metabotropic glutamate receptor 5; Hepatocarcinogenesis; Apoptosis; ERK
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Funding
- State Key Development Program of Basic Research of China [2009CB522205]
- National Natural Science Foundation of the People's Republic of China [81171886, 30873087, 30973406]
- Beijing Municipal Natural Science Foundation [5102011]
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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. (C) 2012 Elsevier Masson SAS. All rights reserved.
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