Activation of the glutamate receptor GRM1 enhances angiogenic signaling to drive melanoma progression.
Glutamate-triggered signal transduction is thought to contribute widely to cancer pathogenesis. In melanoma, overexpression of the metabotropic glutamate receptor (GRM)-1 occurs frequently and its ectopic expression in melanocytes is sufficient for neoplastic transformation. Clinical evaluation of the GRM1 signaling inhibitor riluzole in patients with advanced melanoma has demonstrated tumor regressions that are associated with a suppression of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathways. Together, these results prompted us to investigate the downstream consequences of GRM1 signaling and its disruption in more detail. We found that melanoma cells with enhanced GRM1 expression generated larger tumors in vivo marked by more abundant blood vessels. Media conditioned by these cells in vitro contained relatively higher concentrations of interleukin-8 and VEGF due to GRM1-mediated activation of the AKT-mTOR-HIF1 pathway. In clinical specimens from patients receiving riluzole, we confirmed an inhibition of MAPK and PI3K/AKT activation in posttreatment as compared with pretreatment tumor specimens, which exhibited a decreased density of blood vessels. Together, our results demonstrate that GRM1 activation triggers proangiogenic signaling in melanoma, offering a mechanistic rationale to design treatment strategies for the most suitable combinatorial use of GRM1 inhibitors in patients.
Authors' Affiliations: Division of Surgical Oncology, Department of Surgery; Division of Medical Oncology, Department of Medicine, Rutgers Robert Wood Johnson Medical School; Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway; and Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Yu
Y
Wen
Jiadong
J
Li
Jasmine
J
Koo
Seung-Shick
SS
Shin
Yong
Y
Lin
Byeong-Seon
BS
Jeong
Janice M
JM
Mehnert
Suzie
S
Chen
Karine A
KA
Cohen-Sola
James S
JS
Goydos
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008545:Melanoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D019782:Riluzole / Q000494:pharmacology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D012878:Skin Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D000077022:Survivin; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; C107489:BIRC5 protein, human; C497442:HIF1A protein, human; D006575:Heterocyclic Compounds, 3-Ring; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D051034:Inhibitor of Apoptosis Proteins; D016209:Interleukin-8; C548887:MK 2206; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018094:Receptors, Metabotropic Glutamate; D000077022:Survivin; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D019782:Riluzole; D020123:Sirolimus