title: Disruption of GRM1-mediated signalling using riluzole results in DNA damage in melanoma cells.
abstract: Gain of function of the neuronal receptor, metabotropic glutamate receptor 1 (Grm1), was sufficient to induce melanocytic transformation in vitro and spontaneous melanoma development in vivo when ectopically expressed in melanocytes. The human form of this receptor, GRM1, has been shown to be ectopically expressed in a subset of human melanomas but not benign nevi or normal melanocytes, suggesting that misregulation of GRM1 is involved in the pathogenesis of certain human melanomas. Sustained stimulation of Grm1 by the ligand, glutamate, is required for the maintenance of transformed phenotypes in vitro and tumorigenicity in vivo. In this study, we investigate the mechanism of an inhibitor of glutamate release, riluzole, on human melanoma cells that express metabotropic glutamate receptor 1 (GRM1). Various in vitro assays conducted show that inhibition of glutamate release in several human melanoma cell lines resulted in an increase of oxidative stress and DNA damage response markers.
authors: Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA; Joint Graduate Program of Toxicology, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
authors: Brian A
authors: BA
authors: Wall
authors: Janet
authors: J
authors: Wangari-Talbot
authors: Seung S
authors: SS
authors: Shin
authors: Devora
authors: D
authors: Schiff
authors: Jairo
authors: J
authors: Sierra
authors: Lumeng J
authors: LJ
authors: Yu
authors: Atif
authors: A
authors: Khan
authors: Bruce
authors: B
authors: Haffty
authors: James S
authors: JS
authors: Goydos
authors: Suzie
authors: S
authors: Chen
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001706:Biopsy; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage; D055785:Gene Knockdown Techniques; D018698:Glutamic Acid / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D019782:Riluzole / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C468783:H2AX protein, human; D006657:Histones; D017382:Reactive Oxygen Species; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; D019782:Riluzole; D005978:Glutathione; D000111:Acetylcysteine
keywords: DNA damage; glutamate signalling; melanoma; riluzole