The role of metabotropic glutamate receptor 5 on the stromal cell-derived factor-1/CXCR4 system in oral cancer.
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.
Department of Oral Surgery, Subdivision of Molecular Oral Medicine, Division of Integrated Sciences of Translational Research, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto, Tokushima, Japan.
Nobuyuki
N
Kuribayashi
Daisuke
D
Uchida
Makoto
M
Kinouchi
Natsumi
N
Takamaru
Tetsuya
T
Tamatani
Hirokazu
H
Nagai
Youji
Y
Miyamoto
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018698:Glutamic Acid / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009362:Neoplasm Metastasis; D011725:Pyridines / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology
C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D054377:Chemokine CXCL12; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D019718:Receptors, CXCR4; D013844:Thiazoles; D018698:Glutamic Acid; C121465:6-methyl-2-(phenylethynyl)pyridine