Involvement of metabotropic glutamate receptor�1, a G protein coupled receptor, in melanoma development

Marín, Yarí E.; Chen, Suzie

doi:10.1007/s00109-004-0566-8

Cited by 57 publications

(54 citation statements)

References 126 publications

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“…All those findings indicate that alterations activating RAS/mitogen-activated protein kinase pathway are important events on melanoma development, 27 but also, that tumorigenesis mechanisms are different in different individuals depending on the their sun exposure pattern. mGluR1 is a GCPR, and, therefore, stimulation of this receptor might lead to the activation of MAPK pathway (revised by Marin and Chen 28 ). Until now, there is no evidence of which cascades could be triggered through the activation of this receptor in human melanocytes.…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis of the GRM1 gene in human melanoma susceptibility

et al. 2007

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Data obtained from a mouse model indicated that the ectopic expression of the Grm1 gene is sufficient for transforming melanocytes and causing malignant melanoma in vivo. In addition, it has also been documented that the GRM1 gene is aberrantly expressed in human melanomas. Here we have performed a genetic association study to elucidate whether the GRM1 gene contributes to human melanoma susceptibility. To carry out this study, we initially genotyped 250 melanoma patients and 329 nonselected and nonrelated controls with three single nucleotide polymorphisms, rs854145, rs362962 and rs6923492, located in the intron 1, intron 4 and exon 10 of the GRM1 gene, respectively. To perform sample genotyping, we used pyrosequencing techniques. Regarding rs854145 and rs6923492, there were no differences in genotypic distribution or allelic frequency between patients and controls. However, we observed (i) a higher frequency of patients carrying the C allele of rs362962 than in controls (OR ¼ 1.40, CI ¼ [1.01 -1.95], P ¼ 0.045), and (ii) that difference became greater in a subgroup of patients with a low level of sun exposure and tumours located on the trunk and extremities (OR ¼ 2.10, CI ¼ [1.26 -3.51], P ¼ 0.0039). To confirm these observations, the sample size of both patient and control groups was increased. In total, 464 patients and 561 controls were genotyped for the rs362962 polymorphism. Only the second observation was confirmed (OR ¼ 1.69, CI ¼ [1.16 -2.47], P ¼ 0.0064). Our results suggest that the GRM1 gene may contribute to melanoma susceptibility in that specific group of patients.

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Section: Discussionmentioning

confidence: 99%

Genetic analysis of the GRM1 gene in human melanoma susceptibility

et al. 2007

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“…This property places the EGFR as a downstream element in the signaling pathways of a variety of cell-surface receptors (Carpenter, 1999;Guerrero et al, 2004), most notably GPCRs coupled to Gi or Gq (Carpenter, 1999;Daub et al, 1997;Daub et al, 1996;Gschwind et al, 2001;Hackel et al, 1999;Wetzker and Bohmer, 2003). Abundant evidence suggests that GPCRs could be important regulators of cell growth and under certain circumstances can even act as oncoproteins (Marin and Chen, 2004;Marinissen and Gutkind, 2001;Parnot et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, ectopic expression of a particular GPCR in a cell context that normally lacks the receptor can disrupt cell proliferation control and produce cell transformation in the presence of the corresponding ligand (Marin and Chen, 2004).…”

Section: B P2y 1 R Stimulates Egfr-mediated Mitogenesis Cell Prolifementioning

confidence: 99%

Nucleotide P2Y1 receptor regulates EGF receptor mitogenic signaling and expression in epithelial cells

Buvinic

Bravo‐Zehnder

Boyer

et al. 2007

Journal of Cell Science

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Epidermal growth factor receptor (EGFR) function is transregulated by a variety of stimuli, including agonists of certain G-protein-coupled receptors (GPCRs). One of the most ubiquitous GPCRs is the P2Y1 receptor (P2RY1, hereafter referred to as P2Y1R) for extracellular nucleotides, mainly ADP. Here, we show in tumoral HeLa cells and normal FRT epithelial cells that P2Y1R broadcasts mitogenic signals by transactivating the EGFR. The pathway involves PKC, Src and cell surface metalloproteases. Stimulation of P2Y1R for as little as 15-60 minutes triggers mitogenesis, mirroring the half-life of extracellular ADP. Apyrase degradation of extracellular nucleotides and drug inhibition of P2Y1R, both reduced basal cell proliferation of HeLa and FRT cells, but not MDCK cells, which do not express P2Y1R. Thus, cell-released nucleotides constitute strong mitogenic stimuli, which act via P2Y1R. Strikingly, MDCK cells ectopically expressing P2Y1R display a highly proliferative phenotype that depends on EGFR activity associated with an increased level of EGFR, thus disclosing a novel aspect of GPCR-mediated regulation of EGFR function. These results highlight a role of P2Y1R in EGFR-dependent epithelial cell proliferation. P2Y1R could potentially mediate both trophic stimuli of basally released nucleotides and first-line mitogenic stimulation upon tissue damage. It could also contribute to carcinogenesis and serve as target for antitumor therapies.

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“…In addition, duplex RT-PCR analysis indicated that the mGluR1 (16). The same group characterized a mouse melanoma model, which has implicated the ectopic expression of mGluR1 in melanogenesis and metastasis (16,17). In continuation of these experiments Marín et al (18) showed in mouse melanoma cell lines that stimulation of mGluR1 results in inositol triphosphate (IP 3 ) accumulation and extracellular-regulated kinases 1 and 2 (ERK 1/2) activation, which both could be inhibited by pretreatment of the tumor cells with a mGluR1 subtype-specific competitive antagonist LY367385.…”

Section: Introductionmentioning

confidence: 99%

The non-competitive metabotropic glutamate receptor-1 antagonist CPCCOEt inhibits the in vitro growth of human melanoma

Haas¹,

Pfragner²,

Siegl³

et al. 2007

Oncol Rep

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Abstract. Five decades ago, the dicarboxylic amino acid glutamate became recognized as the major excitatory neurotransmitter in the central nervous system. In recent years, the expression of glutamate receptors was detected also in peripheral, non-neuronal tissues. Furthermore, it was found that glutamate stimulated the proliferation and migration of several peripheral tumor cells, and that glutamate receptor antagonists limited tumor growth. Most of these studies, however, used broad spectrum compounds and/or groupspecific antagonists. Here we report that a selective, noncompetitive metabotropic glutamate receptor-1 antagonist, CPCCOEt (7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester), significantly inhibited the proliferation and modified the morphology of two human melanoma cell lines. These effects were independent of the external glutamate level in the culture medium. In addition, CPCCOEt significantly enhanced the tumoricidal effects of cytostatic drugs. Thus, selective non-competitive metabotropic glutamate receptor antagonists may be used alone and/or with the synergistic effects of chemotherapy, thus enhancing existing therapies of melanoma and possibly other malignancies.

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Involvement of metabotropic glutamate receptor�1, a G protein coupled receptor, in melanoma development

Cited by 57 publications

References 126 publications

Genetic analysis of the GRM1 gene in human melanoma susceptibility

Genetic analysis of the GRM1 gene in human melanoma susceptibility

Nucleotide P2Y1 receptor regulates EGF receptor mitogenic signaling and expression in epithelial cells

The non-competitive metabotropic glutamate receptor-1 antagonist CPCCOEt inhibits the in vitro growth of human melanoma

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