title: Inhibition of metabotropic glutamate receptor 1 suppresses tumor growth and angiogenesis in experimental non-small cell lung cancer.
abstract: Metabotropic glutamate receptor 1 (mGlu1 receptor) is expressed in many cancer cell types as compared to normal counterparts underscoring its potential role in tumor behavior. The aim of present study was to test the role of mGlu1 receptor in experimental non-small cell lung cancer (NSCLC). First, protein expression of mGlu1 receptor was higher in human NSCLC cell lines, including both adenocarcinoma and squamous carcinoma subtypes, when compared to normal bronchial epithelial cells. Inhibition of mGlu1 receptor by BAY36-7620 (an mGlu1 receptor-specific inhibitor) inhibited tumor growth and prolonged survival of mice with tumors of A549 or H1299. Treatment with BAY36-7620 suppressed AKT phosphorylation in A549 tumors and pre-treatment with BAY36-7620 blocked the L-quisqualate (a potent mGlu1 receptor agonist)-induced AKT phosphorylation in A549 cells. Treatment with BAY36-7620 reduced cellular proliferation of A549 cells. Treatment with BAY36-7620 enhanced cleaved PARP levels and reduced protein expression of bcl-2, HIF-1α, and VEGF. In contrast, treatment with L-quisqualate reduced cleaved PARP levels and enhanced protein expression of bcl-2, HIF-1α, VEGF, and IL-8, which was reversed by co-incubation with MK2206 (an AKT inhibitor). Pre-treatment with BAY36-7620 blocked the VEGF-induced AKT phosphorylation in HUVECs. Treatment of HUVECs with L-quisqualate resulted in enhancement of capillary tube formation, which was reversed by co-incubation with MK2206. Furthermore, mGlu1 receptor knockdown suppressed tumor growth and prolonged survival of mice with tumors of A549 or H1299. Collectively, inhibition of mGlu1 receptor suppressed tumor growth and angiogenesis in experimental NSCLC.
authors.affiliation: Department of Thoracic-Cardio Surgery, The First Affiliated Hospital of the General Hospital of PLA, Beijing 100048, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xia
authors.affiliation: Department of Thoracic-Cardio Surgery, The First Affiliated Hospital of the General Hospital of PLA, Beijing 100048, China.
authors.forename: Ying-Nan
authors.initials: YN
authors.lastname: Zhao
authors.affiliation: Department of Thoracic-Cardio Surgery, The First Affiliated Hospital of the General Hospital of PLA, Beijing 100048, China.
authors.forename: Chang-Hai
authors.initials: CH
authors.lastname: Yu
authors.affiliation: Department of Thoracic-Cardio Surgery, The First Affiliated Hospital of the General Hospital of PLA, Beijing 100048, China.
authors.forename: Yun-Long
authors.initials: YL
authors.lastname: Zhao
authors.affiliation: Department of Thoracic Surgery, The General Hospital of PLA, 28 Fuxing Road, Beijing 100853, China. Electronic address: xiahui20133@hotmail.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology* / Q000627:therapeutic use; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C425484:BAY36-7620; D009281:Naphthalenes; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D051057:Proto-Oncogene Proteins c-akt
keywords: Angiogenesis; Metabotropic glutamate receptor 1; Non-small cell lung cancer; Tumor growth