Reaction #1597014
ord-dc0dc9b58b1c4b0583f0a0a11705a44e
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- 1workup.ADDITIONIn addition to involvement in disorders of the central and peripheral nervous system, mGluRs
- 2Otherto result in melanocytic proliferation (Frati, C. et al. 2000; J. Cell. Physiol. 183:364-372)
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In addition to involvement in disorders of the central and peripheral nervous system, mGluRs have recently been implicated as contributing to the development of certain cancers. In recent years, glutamate signaling in cancer has been a focus of investigation. Studies have implicated the involvement of glutamate signaling in tumor development through mGluRs. The role of glutamate signaling in non-neuronal tissues is poorly understood, but studies have shown that a variety of G protein-coupled receptors and G proteins, including those that signal through phosphoinositide hydrolysis and cAMP accumulation, have been implicated in tumorigenesis through either mutational activation or overexpression (Dhanasekaran, N. et al, 1995; Endocr. Rev. 16:259-270; Gutkind, J. 1998; Oncogene 17:1331-1342.). Glutamate has recently been linked to tumor growth in both neuronal and non-neuronal cancers (Takano, T. et al. 2001; Nat. Med. 7:1010-1015; Rzeski, W. et al 2001; Proc. Natl. Acad. Sci. USA 98:6372-6377). Glutamate has been shown to stimulate proliferation of lung carcinoma cells in serum-deprived media, and antagonists of the ionotropic AMPA and NMDA glutamate receptors have been shown to inhibit proliferation and increase cell death in a calcium-dependent manner in a variety of non-neuronal cancers (Rzeski, W. et al 2001; supra). Agonist stimulation of mGluR5 in subconfluent melanocyte cultures has been shown to result in melanocytic proliferation (Frati, C. et al. 2000; J. Cell. Physiol. 183:364-372). It was recently shown that transgenic mice bred to be predisposed to develop multiple melanomas expressed an abundance of mGluR1 in melanoma cells but not in normal melanocytes, and that ectopic expression of mGluR1 was sufficient to cause melanoma (Pollack, P. et al 2003; Nature Genetics 34:108-112). The same study revealed that mGluR1 expression was detected in several human melanoma tumors and cell lines but not in benign nevi (clusters of melanocytes on the skin) or melanocytes. Several cell lines have been developed from independent mouse melanoma tumors (Marin, Y. et al 2005; Neuropharmacol. 49:70-79). These cell lines are useful tools in the studies of signaling events that may be mediated by mGluR1 in transformed melanocytes. In these cells, stimulation of mGluR1 by quisqualate, a Group I competitive glutamate receptor agonist, results in inositol triphosphate (IP3) accumulation, and the activation of the extracellular signal-related protein kinase 1/extracellular signal-related protein kinase 2 (ERK1/2) cell signaling pathway. The extracellular signal-regulated kinase (ERK) signaling pathway is a major determinant in the control of diverse cellular processes such as proliferation, survival, differentiation and motility. This pathway is often up-regulated in human tumors and as such represents an attractive target for the development of anticancer drugs. Because of its multiple roles in the acquisition of a complex malignant phenotype, specific blockade of the ERK pathway is expected to result in not only an antiproliferative effect but also in antimetastatic and antiangiogenic effects in tumor cells. IP3 accumulation and ERK1/2 activation were inhibited by pretreatment of the tumor cells with a mGluR1-specific antagonist (S-2-methyl-4-carboxy-phenylglycine, LY367385) or by dominant negative mutants of mGluR1 demonstrating that stimulation of mGluR1 initiates the ERK pathway but that this action may be inhibited by an antagonist. It was shown that ERK1/2 activation by mGluR1 was PKC-dependent, but cAMP and PKA-independent. These results suggest that mGluR1 and glutamate signaling may be used as novel targets for melanoma therapy (Nankoon et al, 2007 Cancer Res. 67:2298-2305).