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Metabotropic glutamate receptor 1 (Grm1) is an oncogene in epithelial cells

Oncogene volume 32, pages 4366–4376 (2013)Cite this article

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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.

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Acknowledgements

This work was supported by grants R01CA108720 and 09-1143-CCR-EO (SC) and PhD fellowship from the Department of Physiology and Pharmacology, University of Rome "Sapienza", Rome, Itally (EM). We would like to acknowledge the generosity of Dr WM Linehan (Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA) for RCC lines, Dr Daiya Takai (The University of Tokyo Hospital, Tokyo, Japan) for TetR plasmid components, Dr Tony Kong (Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA) for Aperio digital slide scanning/quantification system access and Dr Hao Wu (The Cancer Institute of New Jersey, New Brunswick, NJ, USA) for keen pathological insights.

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Authors and Affiliations

  1. 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

    J J Martino, B A Wall, E Mastrantoni, B J Wilimczyk, S N La Cava & S Chen

  2. Department of Physiology and Pharmacology, University of Rome "Sapienze", Rome, Italy

    E Mastrantoni

  3. Department of Basic Biomedical Sciences, Touro College of Osteopathic Medicine, New York, NY, USA

    K Degenhardt

  4. The Cancer Institute of New Jersey, New Brunswick, NJ, USA

    E White & S Chen

  5. Department of Molecular and Biochemistry, Rutgers University, NJ, USA

    E White

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  1. J J Martino
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Martino, J., Wall, B., Mastrantoni, E. et al. Metabotropic glutamate receptor 1 (Grm1) is an oncogene in epithelial cells. Oncogene 32, 4366–4376 (2013). https://doi.org/10.1038/onc.2012.471

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