title: Metabotropic glutamate receptor 1 acts as a dependence receptor creating a requirement for glutamate to sustain the viability and growth of human melanomas.
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.
authors: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, USA.
authors: T
authors: T
authors: Gelb
authors: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, USA.
authors: S
authors: S
authors: Pshenichkin
authors: Department of Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors: O C
authors: OC
authors: Rodriguez
authors: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, USA.
authors: H A
authors: HA
authors: Hathaway
authors: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, USA.
authors: E
authors: E
authors: Grajkowska
authors: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, USA.
authors: J O
authors: JO
authors: DiRaddo
authors: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, USA.
authors: B
authors: B
authors: Wroblewska
authors: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, USA.
authors: R P
authors: RP
authors: Yasuda
authors: Department of Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors: C
authors: C
authors: Albanese
authors: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, USA.
authors: B B
authors: BB
authors: Wolfe
authors: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, USA.
authors: J T
authors: JT
authors: Wroblewski
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D011804:Quinolines / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*
chemical_list: C495417:(3,4-dihydro-2H-pyrano(2,3)b-quinolin-7-yl)-(cis-4-methoxycyclohexyl) methanone; D011804:Quinolines; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid