Riluzole mediates anti-tumor properties in breast cancer cells independent of metabotropic glutamate receptor-1
- 552 Downloads
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.
KeywordsMetabotropic glutamate receptor-1 Breast cancer Riluzole Voltage-gated sodium channels
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.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
- 8.Banda M, Speyer CL, Semma SN, Osuala KO, Kounalakis N, Torres Torres KE, Barnard NJ, Kim HJ, Sloane BF, Miller FR, Goydos JS, Gorski DH (2014) Metabotropic glutamate receptor-1 contributes to progression in triple negative breast cancer. PLoS One 9(1):e81126. doi: 10.1371/journal.pone.0081126 CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Teh JL, Shah R, La Cava S, Dolfi SC, Mehta MS, Kongara S, Price S, Ganesan S, Reuhl KR, Hirshfield KM, Karantza V, Chen S (2015) Metabotropic glutamate receptor 1 disrupts mammary acinar architecture and initiates malignant transformation of mammary epithelial cells. Breast Cancer Res Treat 151(1):57–73. doi: 10.1007/s10549-015-3365-8 CrossRefPubMedGoogle Scholar
- 15.Pollock PM, Cohen-Solal K, Sood R, Namkoong J, Martino JJ, Koganti A, Zhu H, Robbins C, Makalowska I, Shin SS, Marin Y, Roberts KG, Yudt LM, Chen A, Cheng J, Incao A, Pinkett HW, Graham CL, Dunn K, Crespo-Carbone SM, Mackason KR, Ryan KB, Sinsimer D, Goydos J, Reuhl KR, Eckhaus M, Meltzer PS, Pavan WJ, Trent JM, Chen S (2003) Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia. Nat Genet 34(1):108–112. doi: 10.1038/ng1148 CrossRefPubMedGoogle Scholar
- 17.Le MN, Chan JL, Rosenberg SA, Nabatian AS, Merrigan KT, Cohen-Solal KA, Goydos JS (2010) The glutamate release inhibitor riluzole decreases migration, invasion, and proliferation of melanoma cells. J Invest Dermatol 130(9):2240–2249. doi: 10.1038/jid.2010.126 CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Lee HJ, Wall BA, Wangari-Talbot J, Shin SS, Rosenberg S, Chan JL, Namkoong J, Goydos JS, Chen S (2011) Glutamatergic pathway targeting in melanoma: single-agent and combinatorial therapies. Clin Cancer Res 17(22):7080–7092. doi: 10.1158/1078-0432.CCR-11-0098 CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Wen YY, Li J, Koo J, Shin SS, Lin Y, Jeong BS, Mehnert JM, Chen S, Cohen-Solal K, Goydos JS (2014) Activation of the glutamate receptor GRM1 enhances angiogenic signaling to drive melanoma progression. Cancer Res 74:2499–2509. doi: 10.1158/0008-5472.CAN-13-1531 CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Rosenberg SA, Niglio SA, Salehomoum N, Chan JL, Jeong BS, Wen Y, Li J, Fukui J, Chen S, Shin SS, Goydos JS (2015) Targeting glutamatergic signaling and the PI3 kinase pathway to halt melanoma progression. Transl Oncol 8(1):1–9. doi: 10.1016/j.tranon.2014.11.001 CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Mehta MS, Dolfi SC, Bronfenbrener R, Bilal E, Chen C, Moore D, Lin Y, Rahim H, Aisner S, Kersellius RD, Teh J, Chen S, Toppmeyer DL, Medina DJ, Ganesan S, Vazquez A, Hirshfield KM (2013) Metabotropic glutamate receptor 1 expression and its polymorphic variants associate with breast cancer phenotypes. PLoS ONE 8(7):e69851. doi: 10.1371/journal.pone.0069851 CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Kao J, Salari K, Bocanegra M, Choi YL, Girard L, Gandhi J, Kwei KA, Hernandez-Boussard T, Wang P, Gazdar AF, Minna JD, Pollack JR (2009) Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery. PLoS One 4(7):e6146. doi: 10.1371/journal.pone.0006146 CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Khan AJ, Wall BA, Ahlawat S, Green C, Schiff D, Mehnert JM, Goydos JS, Chen S, Haffty BG (2011) Riluzole enhances ionizing radiation-induced cytotoxicity in human melanoma cells that ectopically express metabotropic glutamate receptor 1 in vitro and in vivo. Clin Cancer Res 17(7):1807–1814. doi: 10.1158/1078-0432.CCR-10-1276 CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Nelson M, Yang M, Millican-Slater R, Brackenbury WJ (2015) Nav1.5 regulates breast tumor growth and metastatic dissemination in vivo. Oncotarget 6(32):32914–32929. doi: 10.18632/oncotarget.5441