title: Metabotropic glutamate receptor 1 (Grm1) is an oncogene in epithelial cells.
abstract: Non-neuronal expression of components of the glutamatergic system has been increasingly observed, and our laboratory previously had demonstrated the etiological role of ectopically expressed metabotropic glutamate receptor 1 (Grm1/mGluR1) in mouse models of melanoma. We hypothesize that inappropriate glutamatergic signaling in other cell types can dysregulate growth leading to transformation and tumorigenesis. As most cancers are carcinomas, we selected an immortalized primary baby mouse kidney (iBMK) cell model to assess whether Grm1 can transform epithelial cells. These iBMK cells, engineered to be immortal yet nontumorigenic and retaining normal epithelial characteristics, were used as recipients for exogenous Grm1 cDNA. Several stable Grm1-expressing clones were isolated and the Grm1-receptors were shown to be functional, as evidenced by the accumulation of second messengers in response to Grm1 agonist. Additionally activated by agonist were mitogen-activated protein kinase (MAPK) and AKT/protein kinase B signaling cascades, the major intracellular pathways shown by many investigators to be critical in melanomagenesis and other neoplasms. These Grm1-iBMK cells exhibited enhanced cell proliferation in in vitro methylthiazolyldiphenyl-tetrazolium bromide (MTT) assays and significant tumorigenicity in in vivo allografts. Persistent Grm1 expression was required for the maintenance of the in vivo tumorigenic phenotype as demonstrated by an inducible Grm1-silencing RNA. These are the first results that indicate that Grm1 can be an oncogene in epithelial cells. In addition, relevance to human disease in the corresponding tumor type of renal cell carcinoma (RCC) may be suggested by observed expression of GRM1/mGluR1 in a number of RCC tumor biopsy samples and cell lines, and the effects of GRM1 modulation on tumorigenicity therein. Moreover, RCC cell lines exhibited elevated levels of extracellular glutamate, and some lines responded to drugs, which modulate the glutamatergic system. These findings imply a possible role for glutamate signaling apparatus in RCC cell growth, and that the glutamatergic system may be a therapeutic target in RCC.
authors.affiliation: Department of Chemical Biology, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Martino
authors.forename: B A
authors.initials: BA
authors.lastname: Wall
authors.forename: E
authors.initials: E
authors.lastname: Mastrantoni
authors.forename: B J
authors.initials: BJ
authors.lastname: Wilimczyk
authors.forename: S N
authors.initials: SN
authors.lastname: La Cava
authors.forename: K
authors.initials: K
authors.lastname: Degenhardt
authors.forename: E
authors.initials: E
authors.lastname: White
authors.forename: S
authors.initials: S
authors.lastname: Chen
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009857:Oncogenes; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D019782:Riluzole / Q000494:pharmacology
chemical_list: D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; D019782:Riluzole; D015544:Inositol 1,4,5-Trisphosphate; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases