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Riluzole mediates anti-tumor properties in breast cancer cells independent of metabotropic glutamate receptor-1

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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.

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Acknowledgments

We are grateful to Dr. Stephen Ethier for kindly providing us with his SUM cell lines and Dr. Fred Miller for kindly providing us with his 4T1 cell line. We are also thankful to Dr. Manohar Ratnam for all his help, insight, and advice throughout this study. This study was supported by a CDMRP BCRP, Breakthrough Award (Level 1) funded by the Department of Defense.

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Authors and Affiliations

  1. 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

    Cecilia L. Speyer, Ali H. Hachem, Miriam A. Bukhsh & David H. Gorski

  2. Kirksville College of Osteopathic Medicine, 800 W Jefferson St, Kirksville, MO, 63501, USA

    Mahdy A. Nassar

  3. College of Medicine, Central Michigan University, 1200 S Franklin St, Mt. Pleasant, MI, 48859, USA

    Ali H. Hachem

  4. Oakland University William Beaumont School of Medicine, 2200 N. Squirrel Rd., Rochester, MI, 48309, USA

    Miriam A. Bukhsh

  5. University of Michigan - Dearborn, 4901 Evergreen Rd., Dearborn, MI, 48128, USA

    Waris S. Jafry & Rafa M. Khansa

  6. Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, 4100 John R St., Detroit, MI, 48201, USA

    David H. Gorski

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  1. Cecilia L. Speyer
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Correspondence to David H. Gorski.

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Speyer, C.L., Nassar, M.A., Hachem, A.H. et al. Riluzole mediates anti-tumor properties in breast cancer cells independent of metabotropic glutamate receptor-1. Breast Cancer Res Treat 157, 217–228 (2016). https://doi.org/10.1007/s10549-016-3816-x

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