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Metabotropic glutamate receptor 1 acts as a dependence receptor creating a requirement for glutamate to sustain the viability and growth of human melanomas

Oncogene volume 34, pages 2711–2720 (2015)Cite this article

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Abstract

Metabotropic glutamate 1 (mGlu) receptor has been proposed as a target for the treatment of metastatic melanoma. Studies have demonstrated that inhibiting the release of glutamate (the natural ligand of mGlu1 receptors), results in a decrease of melanoma tumor growth in mGlu1 receptor-expressing melanomas. Here we demonstrate that mGlu1 receptors, which have been previously characterized as oncogenes, also behave like dependence receptors by creating a dependence on glutamate for sustained cell viability. In the mGlu1 receptor-expressing melanoma cell lines SK-MEL-2 (SK2) and SK-MEL-5 (SK5), we show that glutamate is both necessary and sufficient to maintain cell viability, regardless of underlying genetic mutations. Addition of glutamate increased DNA synthesis, whereas removal of glutamate not only suppressed DNA synthesis but also promoted cell death in SK2 and SK5 melanoma cells. Using genetic and pharmacological inhibitors, we established that this effect of glutamate is mediated by the activation of mGlu1 receptors. The stimulatory potential of mGlu1 receptors was further confirmed in vivo in a melanoma cell xenograft model. In this model, subcutaneous injection of SK5 cells with short hairpin RNA-targeted downregulation of mGlu1 receptors resulted in a decrease in the rate of tumor growth relative to control. We also demonstrate for the first time that a selective mGlu1 receptor antagonist JNJ16259685 ((3,4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone) slows SK2 and SK5 melanoma tumor growth in vivo. Taken together, these data suggest that pharmacological inhibition of mGlu1 receptors may be a novel approach for the treatment of metastatic melanoma.

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Acknowledgements

We thank the Flow Cytometry and Cell Sorting Shared Resource (partially supported by the NIH/NCI grant P30-CA051008), particularly Karen Creswell, and the Histopathology and Tissue Shared Resource (partially supported by the NIH/NCI grant P30-CA051008) at The Georgetown–Lombardi Comprehensive Cancer Center (Georgetown University, Washington, DC, USA) for their expertise. Also, we thank Dr Suzie Chen from Rutgers University for her guidance and generosity and Maria Salinas (Georgetown) for her technical expertise. This work was partially supported by the Pharmaceutical Research and Manufacturers of America Foundation Pre Doctoral Fellowship in Pharmacology/Toxicology to TG, The National Institutes of Health grant NS37436 to JTW and CA129003 to CA.

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Authors and Affiliations

  1. Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, USA,

    T Gelb, S Pshenichkin, H A Hathaway, E Grajkowska, J O DiRaddo, B Wroblewska, R P Yasuda, B B Wolfe & J T Wroblewski

  2. Department of Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA

    O C Rodriguez & C Albanese

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Gelb, T., Pshenichkin, S., Rodriguez, O. et al. Metabotropic glutamate receptor 1 acts as a dependence receptor creating a requirement for glutamate to sustain the viability and growth of human melanomas. Oncogene 34, 2711–2720 (2015). https://doi.org/10.1038/onc.2014.231

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