Activation of the glutamate receptor GRM1 enhances angiogenic signaling to drive melanoma progression

Yu Wen, Jiadong Li, Jasmine Koo, Seung Shick Shin, Yong Lin, Byeong Seon Jeong, Janice M. Mehnert, Suzie Chen, Karine A. Cohen-Sola, James S. Goydos

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


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.Wefound 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.

Original languageEnglish (US)
Pages (from-to)2499-2509
Number of pages11
JournalCancer Research
Issue number9
StatePublished - Jan 5 2014

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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