Expression of glutamate receptor subunits in human cancers

Stepulak, Andrzej; Luksch, Hella; Gebhardt, Christine; Uckermann, Ortrud; Marzahn, Jenny; Sifringer, Marco; Rzeski, Wojciech; Staufner, Christian; Brocke, Katja S.; Turski, Lechosław; Ikonomidou, Chrysanthy

doi:10.1007/s00418-009-0613-1

Cited by 171 publications

(178 citation statements)

References 42 publications

(80 reference statements)

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“…In bone cells, glutamate or NMDA application increases NMDA receptor currents (7). Similarly, mGluR5 expression has been observed in many types of cells other than neurons, including astrocytes, hepatocytes, melanocytes, osteoblast cells (8)(9)(10)(11), fibroblast cells (12), and more recently, stem cells (13,14). In astrocytes, mGluR5 triggers intracellular Ca 2+ release that is potentiated by adenosine receptor activation (8).…”

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confidence: 96%

“…Furthermore, mGluR3 and mGluR5 regulate proliferation, differentiation, and self-renewal of stem cells of different origin (14). Glutamatergic signaling has also been implicated in the biology of cancer (5,12). For example, glutamate has been demonstrated to stimulate proliferation and migration of tumor cell lines (15,16).…”

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confidence: 99%

“…Moreover, NMDA receptor and AMPA receptor antagonists inhibit the ERK pathway, resulting in suppression of cancer growth (16,18). The mGluRs have also been studied, with mGluR5 expression reported in human tumors and cancer cell lines (5,12), such as breast cancer (12), colon cancer (12), sarcomas (10), squamous cell carcinomas (19) and various types of brain tumors (20). Interestingly, ectopic expression of mGluR1 induces melanoma (21).…”

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confidence: 99%

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Expression of the metabotropic glutamate receptor 5 (mGluR5) induces melanoma in transgenic mice

Choi

Chang

Pickel

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Glutamate is the major excitatory neurotransmitter in the mammalian CNS and mediates fast synaptic transmission upon activation of glutamate-gated ion channels. In addition, glutamate modulates a variety of other synaptic responses and intracellular signaling by activating metabotropic glutamate receptors (mGluRs), which are G protein-coupled receptors. The mGluRs are also expressed in nonneuronal tissues and are implicated in a variety of normal biological functions as well as diseases. To study mGluR-activated calcium signaling in neurons, we generated mGluR5 transgenic animals using a Thy1 promoter to drive expression in the forebrain, and one founder unexpectedly developed melanoma. To directly investigate the role of mGluR5 in melanoma formation, we generated mGluR5 transgenic lines under a melanocyte-specific promoter, tyrosinase-related protein 1. A majority of the founders showed a severe phenotype with early onset. Hyperpigmentation of the pinnae and tail could be detected as early as 3-5 d after birth for most of the mGluR5 transgene-positive mice. There was 100% penetrance in the progeny from the tyrosinase-related protein 1-mGluR5 lines generated from founders that developed melanoma. Expression of mGluR5 was detected in melanoma samples by RT-PCR, immunoblotting, and immunohistochemistry. We evaluated the expression of several cancer-related proteins in tumor samples and observed a dramatic increase in the phosphorylation of ERK, implicating ERK as a downstream effector of mGluR5 signaling in tumors. Our findings show that mGluR5-mediated glutamatergic signaling can trigger melanoma in vivo. The aggressive growth and severe phenotype make these mouse lines unique and a potentially powerful tool for therapeutic studies.etabotropic glutamate receptors (mGluRs) are G proteincoupled receptors that are widely expressed in the brain and modulate many diverse signaling pathways. In the CNS, mGluR activation regulates ion channels, mediates slow excitatory and inhibitory responses, modulates neurotransmitter release, and regulates neuronal development and growth (1-3). In addition, various neurological disorders have been attributed to functional impairment of mGluRs in the CNS. The mGluRs (mGluR1-8) are classified into three groups on the basis of sequence identity and pharmacological properties. Group I mGluRs (mGluR1 and mGluR5) are G q -coupled receptors that activate PLCβ, resulting in intracellular Ca 2+ release and protein kinase C (PKC) activation (4).Although glutamate signaling is usually investigated in the context of CNS function, it clearly plays a role in nonneuronal cells as well. In particular, glutamate signaling has been described in astrocytes, cerebral endothelial cells, bone, and skin (5, 6). In bone cells, glutamate or NMDA application increases NMDA receptor currents (7). Similarly, mGluR5 expression has been observed in many types of cells other than neurons, including astrocytes, hepatocytes, melanocytes, osteoblast cells (8-11), fibroblast cells (12), and more recently, stem cells ...

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confidence: 99%

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Expression of the metabotropic glutamate receptor 5 (mGluR5) induces melanoma in transgenic mice

Choi

Chang

Pickel

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, there could be major implications for bone remodeling and chondral mineralization impairment by mGluR system-associated anxiolytic drugs. Stepulak et al (2009) compiled data demonstrating that glutamate receptors are expressed in a variety of cancer cell lines (of neuronal and non-neuronal origin) and tumors, i.e., glioma, colorectal and gastric cancer, oral squamous cell carcinoma, prostate cancer, melanoma and osteosarcoma. It is also believed that the metabolic properties of tumors combined with altered metabolism in patients with cancer contribute to abnormally elevated glutamate plasma concentrations in these patients (Dröge et al, 1988).…”

Section: Bonementioning

confidence: 99%

“…It is also believed that the metabolic properties of tumors combined with altered metabolism in patients with cancer contribute to abnormally elevated glutamate plasma concentrations in these patients (Dröge et al, 1988). In turn, this excess of glutamate may activate its receptors and trigger intracellular signaling pathways, which may affect growth, survival and proliferation of cancer cells (Stepulak et al, 2009). mGluR2 and mGluR7 were found to be expressed in all U87-MG and U343 (glioma), SK-NA-S (neuroblastoma), TE671 (rhabdomyosarcoma/medulloblastoma), MOGGCCM (astrocytoma), SK-LU-1 (lung carcinoma), HT29 and LS180 (colon adenocarcinoma), Jurkat E6.1 (T cell leukemia cells), RPMI 8226 (multiple myeloma), T47D (breast carcinoma), and FTC (thyroid carcinoma) cancer cell lines (Stepulak et al, 2009).…”

Section: Bonementioning

confidence: 99%

Metabotropic Glutamate Receptors in Peripheral Tissues: Implications for Toxicology

Durand¹,

Carniglia²,

Caruso³

et al. 2011

Anxiety Disorders

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G Protein‐Coupled receptors and heterotrimeric G proteins as cancer drivers

Arang

Gutkind

2020

FEBS Letters

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G protein‐coupled receptors (GPCRs) and heterotrimeric G proteins play central roles in a diverse array of cellular processes. As such, dysregulation of GPCRs and their coupled heterotrimeric G proteins can dramatically alter the signalling landscape and functional state of a cell. Consistent with their fundamental physiological functions, GPCRs and their effector heterotrimeric G proteins are implicated in some of the most prevalent human diseases, including a complex disease such as cancer that causes significant morbidity and mortality worldwide. GPCR/G protein‐mediated signalling impacts oncogenesis at multiple levels by regulating tumour angiogenesis, immune evasion, metastasis, and drug resistance. Here, we summarize the growing body of research on GPCRs and their effector heterotrimeric G proteins as drivers of cancer initiation and progression, and as emerging antitumoural therapeutic targets.

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Expression of glutamate receptor subunits in human cancers

Cited by 171 publications

References 42 publications

Expression of the metabotropic glutamate receptor 5 (mGluR5) induces melanoma in transgenic mice

Expression of the metabotropic glutamate receptor 5 (mGluR5) induces melanoma in transgenic mice

Metabotropic Glutamate Receptors in Peripheral Tissues: Implications for Toxicology

G Protein‐Coupled receptors and heterotrimeric G proteins as cancer drivers

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