title: Anti-cancer effect of metabotropic glutamate receptor 1 inhibition in human glioma U87 cells: involvement of PI3K/Akt/mTOR pathway.
abstract: BACKGROUND
  Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors that mediate neuronal excitability and synaptic plasticity in the central nervous system, and emerging evidence suggests a role of mGluRs in the biology of cancer. Previous studies showed that mGluR1 was a potential therapeutic target for the treatment of breast cancer and melanoma, but its role in human glioma has not been determined.
  
  
  METHODS
  In the present study, we investigated the effects of mGluR1 inhibition in human glioma U87 cells using specific targeted small interfering RNA (siRNA) or selective antagonists Riluzole and BAY36-7620. The anti-cancer effects of mGluR1 inhibition were measured by cell viability, lactate dehydrogenase (LDH) release, TUNEL staining, cell cycle assay, cell invasion and migration assays in vitro, and also examined in a U87 xenograft model in vivo.
  
  
  RESULTS
  Inhibition of mGluR1 significantly decreased the cell viability but increased the LDH release in a dose-dependent fashion in U87 cells. These effects were accompanied with the induction of caspase-dependent apoptosis and G0/G1 cell cycle arrest. In addition, the results of Matrigel invasion and cell tracking assays showed that inhibition of mGluR1 apparently attenuated cell invasion and migration in U87 cells. All these anti-cancer effects were ablated by the mGluR1 agonist L-quisqualic acid. The results of western blot analysis showed that mGluR1 inhibition overtly decreased the phosphorylation of PI3K, Akt, mTOR and P70S6K, indicating the mitigated activation of PI3K/Akt/mTOR pathway. Moreover, the anti-tumor activity of mGluR1 inhibition in vivo was also demonstrated in a U87 xenograft glioma model in athymic nude mice.
  
  
  CONCLUSIONS
  The remarkable efficiency of mGluR1 inhibition to induce cell death in U87 cells may find therapeutic application for the treatment of glioma patients.
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central-South University, Changsha, Hunan, China.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Xian-rui
authors.initials: XR
authors.lastname: Yuan
authors.forename: Hao-yu
authors.initials: HY
authors.lastname: Li
authors.forename: Zi-jin
authors.initials: ZJ
authors.lastname: Zhao
authors.forename: Yi-wei
authors.initials: YW
authors.lastname: Liao
authors.forename: Xiang-yu
authors.initials: XY
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Su
authors.forename: Shu-shan
authors.initials: SS
authors.lastname: Sang
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology; D016318:Quisqualic Acid / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019782:Riluzole / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C425484:BAY36-7620; D009281:Naphthalenes; D034741:RNA, Small Interfering; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D019782:Riluzole; D016318:Quisqualic Acid