title: Riluzole mediates anti-tumor properties in breast cancer cells independent of metabotropic glutamate receptor-1.
abstract: Riluzole, the only drug approved by the FDA for treating amyotrophic lateral sclerosis, inhibits melanoma proliferation through its inhibitory effect on glutamatergic signaling. We demonstrated that riluzole also inhibits the growth of triple-negative breast cancer (TNBC) and described a role for metabotropic glutamate receptor-1 (GRM1) in regulating TNBC cell growth and progression. However, the role of GRM1 in mediating riluzole's effects in breast cancer has not been fully elucidated. In this study, we seek to determine how much of riluzole's action in breast cancer is mediated through GRM1. We investigated anti-tumor properties of riluzole in TNBC and ER+ cells using cell growth, invasion, and soft-agar assays and compared riluzole activity with GRM1 levels. Using Lentiviral vectors expressing GRM1 or shGRM1, these studies were repeated in cells expressing high or low GRM1 levels where the gene was either silenced or overexpressed. Riluzole inhibited proliferation, invasion, and colony formation in both TNBC and ER+ cells. There was a trend between GRM1 expression in TNBC cells and their response to riluzole in both cell proliferation and invasion assays. However, silencing and overexpression studies had no effect on cell sensitivity to riluzole. Our results clearly suggest a GRM1-independent mechanism through which riluzole mediates its effects on breast cancer cells. Understanding the mechanism by which riluzole mediates breast cancer progression will be useful in identifying new therapeutic targets for treating TNBC and in facilitating stratification of patients in clinical trials using riluzole in conjunction with conventional therapy.
authors.affiliation: Michael and Marian Ilitch Department of Surgery, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Institute, 4100 John R St., Detroit, MI, 48201, USA.
authors.forename: Cecilia L
authors.initials: CL
authors.lastname: Speyer
authors.affiliation: Kirksville College of Osteopathic Medicine, 800 W Jefferson St, Kirksville, MO, 63501, USA.
authors.forename: Mahdy A
authors.initials: MA
authors.lastname: Nassar
authors.affiliation: Michael and Marian Ilitch Department of Surgery, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Institute, 4100 John R St., Detroit, MI, 48201, USA.|College of Medicine, Central Michigan University, 1200 S Franklin St, Mt. Pleasant, MI, 48859, USA.
authors.forename: Ali H
authors.initials: AH
authors.lastname: Hachem
authors.affiliation: Michael and Marian Ilitch Department of Surgery, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Institute, 4100 John R St., Detroit, MI, 48201, USA.|Oakland University William Beaumont School of Medicine, 2200 N. Squirrel Rd., Rochester, MI, 48309, USA.
authors.forename: Miriam A
authors.initials: MA
authors.lastname: Bukhsh
authors.affiliation: University of Michigan - Dearborn, 4901 Evergreen Rd., Dearborn, MI, 48128, USA.
authors.forename: Waris S
authors.initials: WS
authors.lastname: Jafry
authors.affiliation: University of Michigan - Dearborn, 4901 Evergreen Rd., Dearborn, MI, 48128, USA.
authors.forename: Rafa M
authors.initials: RM
authors.lastname: Khansa
authors.affiliation: Michael and Marian Ilitch Department of Surgery, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Institute, 4100 John R St., Detroit, MI, 48201, USA. david.gorski@wayne.edu.|Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, 4100 John R St., Detroit, MI, 48201, USA. david.gorski@wayne.edu.
authors.forename: David H
authors.initials: DH
authors.lastname: Gorski
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics* / Q000378:metabolism; D019782:Riluzole / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D019782:Riluzole
keywords: Breast cancer; Metabotropic glutamate receptor-1; Riluzole; Voltage-gated sodium channels