<b>Conclusion:</b> The non-toxic radiopharmaceuticals <sup>131</sup>I-IITM and <sup>211</sup>At-AITM are useful high-precision TRT agents that can be used to target the oncoprotein mGluR1 for melanoma therapy.
Using the melanoma mouse model Tg(Grm1), MIA-deficient mice supported the impact of MIA on senescence by showing a significantly earlier tumor onset compared to controls.
If BRaf<sup>V600E</sup> is turned on first, Grm1 expression can be induced, but this is not sufficient to result in development of melanoma; the cells undergo senescence.
Riluzole noncompetitive metabotropic glutamate receptor 1 (mGluR1) antagonist, commonly used to treat patients with amyotrophic lateral sclerosis (ALS), has shown some antineoplastic properties against melanoma, breast and prostate cancer.
Further, we discuss the evolution of riluzole, a glutamate release inhibitor approved for amyotrophic lateral sclerosis (ALS), but now fashioned as an mGluR1 inhibitor for melanoma therapy and as a radio-sensitizer for tumors that have metastasized to the brain.
Taken together, these data demonstrate that the approaches commonly used to study mGlu1 receptor function and signaling in other systems may be inappropriate for studying mGlu1 receptor-mediated melanoma cell viability.
Non-neuronal expression of components of the glutamatergic system has been increasingly observed, and our laboratory previously had demonstrated the etiological role of ectopically expressed metabotropic glutamate receptor 1 (Grm1/mGluR1) in mouse models of melanoma.
Here, we report that melanoma tumor cell lines require wild-type SOX10 expression for proliferation and SOX10 haploinsufficiency reduces melanoma initiation in the metabotropic glutamate receptor 1 (Grm1(Tg)) transgenic mouse model.
We also demonstrate that riluzole-induced Smad linker phosphorylation is independent of the expression of the metabotropic glutamate receptor 1 (GRM1), which is one of the glutamate receptors whose involvement in human melanoma has been documented.
These results reinforce earlier observations where a reduction in cell growth in vitro and tumorigenesis in vivo were correlated with decreased GRM1 activities by pharmacologic inhibitors of the receptor, supporting the notion that GRM1 plays a role in the maintenance of transformed phenotypes in human melanoma cells in vitro and in vivo and could be a potential therapeutic target for the treatment of melanoma.
Here, we demonstrate that the established Tg(Grm1)EPv melanoma mouse model exhibits more extensive metastasis into distant organs than previously described.
We previously described the oncogenic properties of metabotropic glutamate receptor 1 (Grm1), a G-protein-coupled receptor in melanoma development in vivo.
Ectopic expression of GRM1 in murine melanocytes results in transformation into a form of melanoma, and more than 60% of human melanoma samples tested ectopically express GRM1.
Treatment of GRM1-expressing human melanoma cells with a GRM1 antagonist (LY367385 or BAY36-7620) or a glutamate release inhibitor (riluzole) leads to a suppression of cell proliferation as well as a decrease in levels of extracellular glutamate.
Ectopic expression of GRM1 was also detected in a subset of human melanoma cell lines and biopsies, suggesting that aberrant expression of GRM1 in melanocytes may contribute to the development of human melanoma.
Studies of our transgenic mouse melanoma model (TG-3) revealed that ectopic expression of Grm1 in melanocytes is sufficient to induce melanoma development in vivo [P.M. Pollock, K. Cohen-Solal, R. Sood, J. Namkoong, J.J. Martino, A. Koganti, H. Zhu, C. Robbins, I. Makalowska, S.S. Shin, Y. Marin, K.G.Roberts, L.M.Yudt, A. Chen, J. Cheng, A. Incao, H.W.Pinkett, C.L.Graham, K. Dunn, S.M.Crespo-Carbone, K.R.Mackason, K.B.Ryan, D. Sinsimer, J. Goydos, K.R.Reuhl, M. Eckhaus, P.S.Meltzer, W.J.Pavan, J.M.Trent, S. Chen, Nat.Genet.34 (2003) 108-112.].