The Experts below are selected from a list of 56127 Experts worldwide ranked by ideXlab platform
Cecilia L Speyer - One of the best experts on this subject based on the ideXlab platform.
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metabotropic Glutamate Receptor 1 regulates inflammation in triple negative breast cancer
Scientific Reports, 2018Co-Authors: Rachel E Sexton, David H. Gorski, Ali H. Hachem, Miriam A. Bukhsh, Ali A Assi, Cecilia L SpeyerAbstract:Breast cancer remains a major cause of death among women. 15% of these cancers are triple negative breast cancer (TNBC), an aggressive subtype of breast cancer for which no current effective targeted therapy exists. We have previously demonstrated a role for mGluR1 in mediating tumor cell growth, endothelial cell proliferation, and tumor-induced angiogenesis in TNBC. In this study, we explore a role for mGluR1 in regulating inflammation in TNBC. GRM1 expression was silenced in MDA-MB-231 cells to study changes in expression of inflammatory genes regulated by mGluR1. Results were confirmed by ELISA using GRM1-silenced and overexpressed cells and mGluR1 inhibitors. A functional role for these differentially expressed genes was determined in vitro and in vivo. 131 genes were differentially expressed in GRM1-silenced MDA-MB-231 cells, with some of these falling into four major canonical pathways associated with acute inflammation, specifically leukocyte migration/chemotaxis. Upregulation of three of these genes (CXCL1, IL6, IL8) and their corresponding protein was confirmed by qPCR analysis and ELISA in GRM1-manipulated TNBC cells. Upregulation of these cytokines enhanced endothelial adhesion and transmigration of neutrophils in co-culture assays and in 4T1 mouse tumors. Our results suggest mGluR1 may serve as a novel endogenous regulator of inflammation in TNBC.
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Riluzole mediates anti-tumor properties in breast cancer cells independent of metabotropic Glutamate Receptor-1
Breast Cancer Research and Treatment, 2016Co-Authors: Cecilia L Speyer, Mahdy A. Nassar, Ali H. Hachem, Miriam A. Bukhsh, Waris S. Jafry, Rafa M. Khansa, David H. GorskiAbstract:Riluzole, the only drug approved by the FDA for treating amyotrophic lateral sclerosis, inhibits melanoma proliferation through its inhibitory effect on Glutamatergic signaling. We demonstrated that riluzole also inhibits the growth of triple-negative breast cancer (TNBC) and described a role for metabotropic Glutamate Receptor-1 ( GRM1 ) in regulating TNBC cell growth and progression. However, the role of GRM1 in mediating riluzole’s effects in breast cancer has not been fully elucidated. In this study, we seek to determine how much of riluzole’s action in breast cancer is mediated through GRM1 . We investigated anti-tumor properties of riluzole in TNBC and ER+ cells using cell growth, invasion, and soft-agar assays and compared riluzole activity with GRM1 levels. Using Lentiviral vectors expressing GRM1 or sh GRM1 , these studies were repeated in cells expressing high or low GRM1 levels where the gene was either silenced or overexpressed. Riluzole inhibited proliferation, invasion, and colony formation in both TNBC and ER+ cells. There was a trend between GRM1 expression in TNBC cells and their response to riluzole in both cell proliferation and invasion assays. However, silencing and overexpression studies had no effect on cell sensitivity to riluzole. Our results clearly suggest a GRM1 -independent mechanism through which riluzole mediates its effects on breast cancer cells. Understanding the mechanism by which riluzole mediates breast cancer progression will be useful in identifying new therapeutic targets for treating TNBC and in facilitating stratification of patients in clinical trials using riluzole in conjunction with conventional therapy.
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metabotropic Glutamate Receptor 1 as a novel target for the antiangiogenic treatment of breast cancer
PLOS ONE, 2014Co-Authors: Cecilia L Speyer, John A Devries, Ali H. Hachem, Ali A Assi, Jennifer Johnson, David H. GorskiAbstract:Metabotropic Glutamate Receptors (mGluRs) are normally expressed in the central nervous system, where they mediate neuronal excitability and neurotransmitter release. Certain cancers, including melanoma and gliomas, express various mGluR subtypes that have been implicated as playing a role in disease progression. Recently, we detected metabotropic Glutamate Receptor-1 (gene: GRM1; protein: mGluR1) in breast cancer and found that it plays a role in the regulation of cell proliferation and tumor growth. In addition to cancer cells, brain endothelial cells express mGluR1. In light of these studies, and because angiogenesis is both a prognostic indicator in cancer correlating with a poorer prognosis and a potential therapeutic target, we explored a potential role for mGluR1 in mediating endothelial cell (EC) proliferation and tumor-induced angiogenesis. GRM1 and mGluR1 were detected in various types of human ECs and, using mGluR1-specific inhibitors or shRNA silencing, we demonstrated that EC growth and Matrigel tube formation are dependent on mGluR1 signaling. In addition, loss of mGluR1 activity leads to reduced angiogenesis in a murine Matrigel sponge implant model as well as a murine tumor model. These results suggest a role for mGluR1 in breast cancer as a pro-angiogenic factor as well as a mediator of tumor progression. They also suggest mGluR1 as a potential new molecular target for the anti-angiogenic therapy of breast cancer.
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metabotropic Glutamate Receptor 1 contributes to progression in triple negative breast cancer
PLOS ONE, 2014Co-Authors: Cecilia L Speyer, Malathi Banda, Sara N Semma, Kingsley Osuala, Nicole Kounalakis, Keila E Torres, Nicola Barnard, Hyunjin J Kim, Bonnie F SloaneAbstract:TNBC is an aggressive breast cancer subtype that does not express hormone Receptors (estrogen and progesterone Receptors, ER and PR) or amplified human epidermal growth factor Receptor type 2 (HER2), and there currently exist no targeted therapies effective against it. Consequently, finding new molecular targets in triple negative breast cancer (TNBC) is critical to improving patient outcomes. Previously, we have detected the expression of metabotropic Glutamate Receptor-1 (gene: GRM1; protein: mGluR1) in TNBC and observed that targeting Glutamatergic signaling inhibits TNBC growth both in vitro and in vivo. In this study, we explored how mGluR1 contributes to TNBC progression, using the isogenic MCF10 progression series, which models breast carcinogenesis from nontransformed epithelium to malignant basal-like breast cancer. We observed that mGluR1 is expressed in human breast cancer and that in MCF10A cells, which model nontransformed mammary epithelium, but not in MCF10AT1 cells, which model atypical ductal hyperplasia, mGluR1 overexpression results in increased proliferation, anchorage-independent growth, and invasiveness. In contrast, mGluR1 knockdown results in a decrease in these activities in malignant MCF10CA1d cells. Similarly, pharmacologic inhibition of Glutamatergic signaling in MCF10CA1d cells results in a decrease in proliferation and anchorage-independent growth. Finally, transduction of MCF10AT1 cells, which express c-Ha-ras, using a lentiviral construct expressing GRM1 results in transformation to carcinoma in 90% of resultant xenografts. We conclude that mGluR1 cooperates with other factors in hyperplastic mammary epithelium to contribute to TNBC progression and therefore propose that Glutamatergic signaling represents a promising new molecular target for TNBC therapy.
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metabotropic Glutamate Receptor 1 a potential therapeutic target for the treatment of breast cancer
Breast Cancer Research and Treatment, 2012Co-Authors: Cecilia L Speyer, Malathi Banda, John A Devries, Tassia Mekani, Jennifer S Smith, David H. GorskiAbstract:Metabotropic Glutamate Receptors are G-protein-coupled Receptors normally expressed in the central nervous system where they mediate neuronal excitability, synaptic plasticity, and feedback inhibition of neurotransmitter release. However, recent data suggest that these Receptors are also expressed and functional in some cancers, most notably melanoma. We detected the expression of metabotropic Glutamate Receptor-1 (gene: GRM1; protein: mGluR1) in triple negative breast cancer cells and evaluated its role in regulating the pro-proliferative phenotype of these cells. mGluR1 inhibitors (Riluzole or BAY36-7620) inhibited the proliferation of triple negative breast cancer cells in a time- and dose-dependent manner and this inhibition correlated with increased apoptosis as demonstrated by increase in PARP cleavage products and Annexin V staining. mGluR1 knockdown using Lentiviral constructs expressing shRNA targeting GRM1 also inhibited proliferation compared to non-silencing controls. In addition, treatment of mice bearing MDA-MB-231 xenografts with Riluzole or BAY36-7620, by intraperitoneal injection, resulted in a significant reduction in tumor volume of up to 80%. Moreover, Riluzole was effective against triple negative breast cancer xenografts in mice at doses equivalent to those currently being used in humans for the treatment of amyotrophic lateral sclerosis. Our observations implicate mGluR1 and Glutamate signaling as a promising new molecular target for the treatment of breast cancer. Even more promising, Riluzole, because it is an oral drug that can be administered with low toxicity, represents a promising approach in the treatment of triple negative breast cancer.
David H. Gorski - One of the best experts on this subject based on the ideXlab platform.
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metabotropic Glutamate Receptor 1 regulates inflammation in triple negative breast cancer
Scientific Reports, 2018Co-Authors: Rachel E Sexton, David H. Gorski, Ali H. Hachem, Miriam A. Bukhsh, Ali A Assi, Cecilia L SpeyerAbstract:Breast cancer remains a major cause of death among women. 15% of these cancers are triple negative breast cancer (TNBC), an aggressive subtype of breast cancer for which no current effective targeted therapy exists. We have previously demonstrated a role for mGluR1 in mediating tumor cell growth, endothelial cell proliferation, and tumor-induced angiogenesis in TNBC. In this study, we explore a role for mGluR1 in regulating inflammation in TNBC. GRM1 expression was silenced in MDA-MB-231 cells to study changes in expression of inflammatory genes regulated by mGluR1. Results were confirmed by ELISA using GRM1-silenced and overexpressed cells and mGluR1 inhibitors. A functional role for these differentially expressed genes was determined in vitro and in vivo. 131 genes were differentially expressed in GRM1-silenced MDA-MB-231 cells, with some of these falling into four major canonical pathways associated with acute inflammation, specifically leukocyte migration/chemotaxis. Upregulation of three of these genes (CXCL1, IL6, IL8) and their corresponding protein was confirmed by qPCR analysis and ELISA in GRM1-manipulated TNBC cells. Upregulation of these cytokines enhanced endothelial adhesion and transmigration of neutrophils in co-culture assays and in 4T1 mouse tumors. Our results suggest mGluR1 may serve as a novel endogenous regulator of inflammation in TNBC.
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Riluzole mediates anti-tumor properties in breast cancer cells independent of metabotropic Glutamate Receptor-1
Breast Cancer Research and Treatment, 2016Co-Authors: Cecilia L Speyer, Mahdy A. Nassar, Ali H. Hachem, Miriam A. Bukhsh, Waris S. Jafry, Rafa M. Khansa, David H. GorskiAbstract:Riluzole, the only drug approved by the FDA for treating amyotrophic lateral sclerosis, inhibits melanoma proliferation through its inhibitory effect on Glutamatergic signaling. We demonstrated that riluzole also inhibits the growth of triple-negative breast cancer (TNBC) and described a role for metabotropic Glutamate Receptor-1 ( GRM1 ) in regulating TNBC cell growth and progression. However, the role of GRM1 in mediating riluzole’s effects in breast cancer has not been fully elucidated. In this study, we seek to determine how much of riluzole’s action in breast cancer is mediated through GRM1 . We investigated anti-tumor properties of riluzole in TNBC and ER+ cells using cell growth, invasion, and soft-agar assays and compared riluzole activity with GRM1 levels. Using Lentiviral vectors expressing GRM1 or sh GRM1 , these studies were repeated in cells expressing high or low GRM1 levels where the gene was either silenced or overexpressed. Riluzole inhibited proliferation, invasion, and colony formation in both TNBC and ER+ cells. There was a trend between GRM1 expression in TNBC cells and their response to riluzole in both cell proliferation and invasion assays. However, silencing and overexpression studies had no effect on cell sensitivity to riluzole. Our results clearly suggest a GRM1 -independent mechanism through which riluzole mediates its effects on breast cancer cells. Understanding the mechanism by which riluzole mediates breast cancer progression will be useful in identifying new therapeutic targets for treating TNBC and in facilitating stratification of patients in clinical trials using riluzole in conjunction with conventional therapy.
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metabotropic Glutamate Receptor 1 as a novel target for the antiangiogenic treatment of breast cancer
PLOS ONE, 2014Co-Authors: Cecilia L Speyer, John A Devries, Ali H. Hachem, Ali A Assi, Jennifer Johnson, David H. GorskiAbstract:Metabotropic Glutamate Receptors (mGluRs) are normally expressed in the central nervous system, where they mediate neuronal excitability and neurotransmitter release. Certain cancers, including melanoma and gliomas, express various mGluR subtypes that have been implicated as playing a role in disease progression. Recently, we detected metabotropic Glutamate Receptor-1 (gene: GRM1; protein: mGluR1) in breast cancer and found that it plays a role in the regulation of cell proliferation and tumor growth. In addition to cancer cells, brain endothelial cells express mGluR1. In light of these studies, and because angiogenesis is both a prognostic indicator in cancer correlating with a poorer prognosis and a potential therapeutic target, we explored a potential role for mGluR1 in mediating endothelial cell (EC) proliferation and tumor-induced angiogenesis. GRM1 and mGluR1 were detected in various types of human ECs and, using mGluR1-specific inhibitors or shRNA silencing, we demonstrated that EC growth and Matrigel tube formation are dependent on mGluR1 signaling. In addition, loss of mGluR1 activity leads to reduced angiogenesis in a murine Matrigel sponge implant model as well as a murine tumor model. These results suggest a role for mGluR1 in breast cancer as a pro-angiogenic factor as well as a mediator of tumor progression. They also suggest mGluR1 as a potential new molecular target for the anti-angiogenic therapy of breast cancer.
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metabotropic Glutamate Receptor 1 a potential therapeutic target for the treatment of breast cancer
Breast Cancer Research and Treatment, 2012Co-Authors: Cecilia L Speyer, Malathi Banda, John A Devries, Tassia Mekani, Jennifer S Smith, David H. GorskiAbstract:Metabotropic Glutamate Receptors are G-protein-coupled Receptors normally expressed in the central nervous system where they mediate neuronal excitability, synaptic plasticity, and feedback inhibition of neurotransmitter release. However, recent data suggest that these Receptors are also expressed and functional in some cancers, most notably melanoma. We detected the expression of metabotropic Glutamate Receptor-1 (gene: GRM1; protein: mGluR1) in triple negative breast cancer cells and evaluated its role in regulating the pro-proliferative phenotype of these cells. mGluR1 inhibitors (Riluzole or BAY36-7620) inhibited the proliferation of triple negative breast cancer cells in a time- and dose-dependent manner and this inhibition correlated with increased apoptosis as demonstrated by increase in PARP cleavage products and Annexin V staining. mGluR1 knockdown using Lentiviral constructs expressing shRNA targeting GRM1 also inhibited proliferation compared to non-silencing controls. In addition, treatment of mice bearing MDA-MB-231 xenografts with Riluzole or BAY36-7620, by intraperitoneal injection, resulted in a significant reduction in tumor volume of up to 80%. Moreover, Riluzole was effective against triple negative breast cancer xenografts in mice at doses equivalent to those currently being used in humans for the treatment of amyotrophic lateral sclerosis. Our observations implicate mGluR1 and Glutamate signaling as a promising new molecular target for the treatment of breast cancer. Even more promising, Riluzole, because it is an oral drug that can be administered with low toxicity, represents a promising approach in the treatment of triple negative breast cancer.
Suzie Chen - One of the best experts on this subject based on the ideXlab platform.
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metabolic signaling cascades prompted by glutaminolysis in cancer
Cancers, 2020Co-Authors: Raj Shah, Suzie ChenAbstract:Aberrant Glutamatergic signaling has been implicated in altered metabolic activity and the demand to synthesize biomass in several types of cancer including melanoma. In the last decade, there has been a significant contribution to our understanding of metabolic pathways. An increasing number of studies are now emphasizing the importance of Glutamate functioning as a signaling molecule and a building block for cancer progression. To that end, our group has previously illustrated the role of Glutamatergic signaling mediated by metabotropic Glutamate Receptor 1 (GRM1) in neoplastic transformation of melanocytes in vitro and spontaneous development of metastatic melanoma in vivo. Glutamate, the natural ligand of GRM1, is one of the most abundant amino acids in humans and the predominant excitatory neurotransmitter in the central nervous system. Elevated levels of glutaminolytic mitochondrial tricarboxylic acid (TCA) cycle intermediates, especially Glutamate, have been reported in numerous cancer cells. Herein, we highlight and critically review metabolic bottlenecks that are prevalent during tumor evolution along with therapeutic implications of limiting Glutamate bioavailability in tumors.
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concurrent targeting of glutaminolysis and metabotropic Glutamate Receptor 1 grm1 reduces Glutamate bioavailability in grm1 melanoma
Cancer Research, 2019Co-Authors: Raj Shah, Simar J Singh, Kevinn Eddy, Fabian V Filipp, Suzie ChenAbstract:Aberrant Glutamatergic signaling has been implicated in altered metabolic activity in many cancer types, including malignant melanoma. Previously, we have illustrated the role of metabotropic Glutamate Receptor 1 (GRM1) in neoplastic transformation of melanocytes in vitro and spontaneous metastatic melanoma in vivo. In this study, we showed that autocrine stimulation constitutively activates the GRM1 Receptor and its downstream mitogenic signaling. GRM1-activated (GRM1+) melanomas exhibited significantly increased expression of glutaminase (GLS), which catalyzes the first step in the conversion of glutamine to Glutamate. In cultured GRM1+ melanoma cell lines, CB-839, a potent, selective, and orally bioavailable inhibitor of GLS, suppressed cell proliferation, while riluzole, an inhibitor of Glutamate release, promoted apoptotic cell death in vitro and in vivo. Combined treatment with CB-839 and riluzole treatment proved to be superior to single-agent treatment, restricting Glutamate bioavailability and leading to effective suppression of tumor cell proliferation in vitro and tumor progression in vivo. Hyperactivation of GRM1 in malignant melanoma is an oncogenic driver, which acts independently of canonical melanoma proto-oncogenes, BRAF or NRAS. Overall, these results indicate that expression of GRM1 promotes a metabolic phenotype that supports increased Glutamate production and autocrine Glutamatergic signaling, which can be pharmacologically targeted by decreasing Glutamate bioavailability and the GLS-dependent glutamine to Glutamate conversion. SIGNIFICANCE: These findings demonstrate that targeting glutaminolytic Glutamate bioavailability is an effective therapeutic strategy for GRM1-activated tumors.
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riluzole exerts distinct antitumor effects from a metabotropic Glutamate Receptor 1 specific inhibitor on breast cancer cells
Oncotarget, 2017Co-Authors: Sonia C Dolfi, Daniel J Medina, Aparna Kareddula, Bhavna S Paratala, Ashley Rose, Jatinder Dhami, Suzie Chen, Shridar Ganesan, Gillian Mackay, Alexei VazquezAbstract:Recent evidence suggests that Glutamate signaling plays an important role in cancer. Riluzole is a Glutamate release inhibitor and FDA-approved drug for the treatment of amyotrophic lateral sclerosis. It has been investigated as an inhibitor of cancer cell growth and tumorigenesis with the intention of repurposing it for the treatment of cancer. Riluzole is thought to act by indirectly inhibiting Glutamate signaling. However, the specific effects of riluzole in breast cancer cells are not well understood. In this study, the anti-cancer effects of riluzole were explored in a panel of breast cancer cell lines in comparison to the metabotropic Glutamate Receptor 1-specific inhibitor BAY 36-7620. While both drugs inhibited breast cancer cell proliferation, there were distinct functional effects suggesting that riluzole action may be metabotropic Glutamate Receptor 1-independent. Riluzole induced mitotic arrest independent of oxidative stress while BAY 36-7620 had no measurable effect on mitosis. BAY 36-7620 had a more pronounced and significant effect on DNA damage than riluzole. Riluzole altered cellular metabolism as demonstrated by changes in oxidative phosphorylation and cellular metabolite levels. These results provide a better understanding of the functional action of riluzole in the treatment of breast cancer.
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Supplementary Methods Animals
2015Co-Authors: Benjamin Voisin, Suzie Chen, David Gabriel Mairhofer, Patrizia Stoitzner, Christopher George, Vincent FlacherAbstract:C57BL/6 mice with transgenic overexpression of RANK under the control of the S100A8 promotor active in hair follicles were bred heterozygously (1,2). The transgenic mouse strain tg(Grm1)EPv, were developed by Dr. Suzie Chen (Chemical Biology\u2028Lab for Cancer Research, Rutgers University, Piscataway, NJ, USA) (3). They develop spontaneous melanocytic tumors around the 4th month of life, due to over-expression of the metabotropic Glutamate Receptor 1 (Grm1) under control of the melanocyte-specific dopachrome tautomerase promoter. Evan’s blue injection Mice were anesthetized by isoflurane inhalation before being injected subcutaneously in the proximal part of the tail with 5 % Evan’s blue diluted in PBS buffer. After 3 h, mice were sacrificed and the color of sciatic (proximal) and brachial (distal) LNs was visually evaluated. Imiquimod-induced skin inflammation Mice were anesthetized by isoflurane inhalation and skin inflammation was triggered by one application of 2.5mg imiquimod (AldaraTM) on tail skin. Mice were sacrificed 2, 5 or 8 days post-stimulation. DC subsets in sciatic and brachial LNs were assessed by flow cytometry analysis. Fluorescent tracking of skin-derived LCs in skin-draining LN
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metabotropic Glutamate Receptor 1 grm1 is an oncogene in epithelial cells
Oncogene, 2013Co-Authors: J J Martino, Brian A Wall, E Mastrantoni, B J Wilimczyk, S N La Cava, Kurt Degenhardt, Eileen White, Suzie ChenAbstract: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. We hypothesize that inappropriate Glutamatergic signaling in other cell types can dysregulate growth leading to transformation and tumorigenesis. As most cancers are carcinomas, we selected an immortalized primary baby mouse kidney (iBMK) cell model to assess whether Grm1 can transform epithelial cells. These iBMK cells, engineered to be immortal yet nontumorigenic and retaining normal epithelial characteristics, were used as recipients for exogenous Grm1 cDNA. Several stable Grm1-expressing clones were isolated and the Grm1-Receptors were shown to be functional, as evidenced by the accumulation of second messengers in response to Grm1 agonist. Additionally activated by agonist were mitogen-activated protein kinase (MAPK) and AKT/protein kinase B signaling cascades, the major intracellular pathways shown by many investigators to be critical in melanomagenesis and other neoplasms. These Grm1-iBMK cells exhibited enhanced cell proliferation in in vitro methylthiazolyldiphenyl-tetrazolium bromide (MTT) assays and significant tumorigenicity in in vivo allografts. Persistent Grm1 expression was required for the maintenance of the in vivo tumorigenic phenotype as demonstrated by an inducible Grm1-silencing RNA. These are the first results that indicate that Grm1 can be an oncogene in epithelial cells. In addition, relevance to human disease in the corresponding tumor type of renal cell carcinoma (RCC) may be suggested by observed expression of GRM1/mGluR1 in a number of RCC tumor biopsy samples and cell lines, and the effects of GRM1 modulation on tumorigenicity therein. Moreover, RCC cell lines exhibited elevated levels of extracellular Glutamate, and some lines responded to drugs, which modulate the Glutamatergic system. These findings imply a possible role for Glutamate signaling apparatus in RCC cell growth, and that the Glutamatergic system may be a therapeutic target in RCC.
Kohji Fukunaga - One of the best experts on this subject based on the ideXlab platform.
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spiro imidazo 1 2 a pyridine 3 2 indan 2 3h one zset1446 st101 treatment rescues olfactory bulbectomy induced memory impairment by activating ca2 calmodulin kinase ii and protein kinase c in mouse hippocampus
Journal of Pharmacology and Experimental Therapeutics, 2008Co-Authors: Feng Han, Norifumi Shioda, Shigeki Moriguchi, Yui Yamamoto, Alisa Ali Y Raie, Yoshimasa Yamaguchi, Masataka Hino, Kohji FukunagaAbstract:Olfactory bulbectomy (OBX) in mice elicits impaired memory and cognitive functions. Here, we found that chronic oral administration of spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446/ST101) (0.1-1 mg/kg/day), a novel cognitive enhancer, significantly improved memory deficits as assessed by Y-maze and novel object recognition tasks in OBX mice. Immunostaining of cholinergic neurons in the medial septum by using an anti-choline acetyltransferase antibody indicated that chronic ZSET1446 treatment did not rescue cholinergic neurons. However, chronic treatment significantly restored OBX-induced decreases both in calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC) phosphorylation without improving decreased extracellular signal-regulated kinase phosphorylation in the hippocampal CA1 region. Consistent with enhanced CaMKII and PKC phosphorylation, ZSET1446 treatment improved Glutamate Receptor 1 (Ser-831) phosphorylation in the hippocampal CA1 region. ZSET1446 treatment also significantly rescued impaired long-term potentiation (LTP) in the hippocampal CA1 region of OBX mice. Taken together, the cognition-enhancing effect of ZSET1446 is probably mediated in part by stimulation of CaMKII and PKC activities, which in turn rescue impaired hippocampal LTP in OBX mice.
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spiro imidazo 1 2 a pyridine 3 2 indan 2 3h one zset1446 st101 treatment rescues olfactory bulbectomy induced memory impairment by activating ca2 calmodulin kinase ii and protein kinase c in mouse hippocampus
Journal of Pharmacology and Experimental Therapeutics, 2008Co-Authors: Norifumi Shioda, Shigeki Moriguchi, Yui Yamamoto, Alisa Ali Y Raie, Yoshimasa Yamaguchi, Masataka Hino, Kohji FukunagaAbstract:Olfactory bulbectomy (OBX) in mice elicits impaired memory and cognitive functions. Here, we found that chronic oral administration of spiro[imidazo[1,2- a ]pyridine-3,2-indan]-2(3 H )-one (ZSET1446/ST101) (0.1–1 mg/kg/day), a novel cognitive enhancer, significantly improved memory deficits as assessed by Y-maze and novel object recognition tasks in OBX mice. Immunostaining of cholinergic neurons in the medial septum by using an anti-choline acetyltransferase antibody indicated that chronic ZSET1446 treatment did not rescue cholinergic neurons. However, chronic treatment significantly restored OBX-induced decreases both in calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC) phosphorylation without improving decreased extracellular signal-regulated kinase phosphorylation in the hippocampal CA1 region. Consistent with enhanced CaMKII and PKC phosphorylation, ZSET1446 treatment improved Glutamate Receptor 1 (Ser-831) phosphorylation in the hippocampal CA1 region. ZSET1446 treatment also significantly rescued impaired long-term potentiation (LTP) in the hippocampal CA1 region of OBX mice. Taken together, the cognition-enhancing effect of ZSET1446 is probably mediated in part by stimulation of CaMKII and PKC activities, which in turn rescue impaired hippocampal LTP in OBX mice.
Thomas R Soderling - One of the best experts on this subject based on the ideXlab platform.
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identification of the ca2 calmodulin dependent protein kinase ii regulatory phosphorylation site in the alpha amino 3 hydroxyl 5 methyl 4 isoxazole propionate type Glutamate Receptor
Journal of Biological Chemistry, 1997Co-Authors: Andres Barria, Victor A Derkach, Thomas R SoderlingAbstract:Abstract Ca2+/CaM-dependent protein kinase II (CaM-KII) can phosphorylate and potentiate responses of α-amino3-hydroxyl-5-methyl-4-isoxazole-propionate-type Glutamate Receptors in a number of systems, and recent studies implicate this mechanism in long term potentiation, a cellular model of learning and memory. In this study we have identified this CaM-KII regulatory site using deletion and site-specific mutants of Glutamate Receptor 1 (GluR1). Only mutations affecting Ser831 altered the 32P peptide maps of GluR1 from HEK-293 cells co-expressing an activated CaM-KII. Likewise, when CaM-KII was infused into cells expressing GluR1, the Ser831 to Ala mutant failed to show potentiation of the GluR1 current. The Ser831 site is specific to GluR1, and CaM-KII did not phosphorylate or potentiate current in cells expressing GluR2, emphasizing the importance of the GluR1 subunit in this regulatory mechanism. Because Ser831 has previously been identified as a protein kinase C phosphorylation site (Roche, K. W., O’Brien, R. J., Mammen, A. L., Bernhardt, J., and Huganir, R. L. (1996) Neuron 16, 1179–1188), this raises the possibility of synergistic interactions between CaM-KII and protein kinase C in regulating synaptic plasticity.
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identification of a ca2 calmodulin dependent protein kinase ii regulatory phosphorylation site in non n methyl d aspartate Glutamate Receptors
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Jerrel L Yakel, Prabhakar Vissavajjhala, Victor A Derkach, Debra A Brickey, Thomas R SoderlingAbstract:Abstract Glutamate Receptor ion channels are colocalized in postsynaptic densities with Ca2+/calmodulin-dependent protein kinase II (CaM-kinase II), which can phosphorylate and strongly enhance non-N-methyl-D-aspartate (NMDA) Glutamate Receptor current. In this study, CaM-kinase II enhanced kainate currents of expressed Glutamate Receptor 6 in 293 cells and of wild-type Glutamate Receptor 1, but not the Ser-627 to Ala mutant, in Xenopus oocytes. A synthetic peptide corresponding to residues 620-638 in GluR1 was phosphorylated in vitro by CaM-kinase II but not by cAMP-dependent protein kinase or protein kinase C. The 32P-labeled peptide map of this synthetic peptide appears to be the same as the two-dimensional peptide map of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) Glutamate Receptors phosphorylated in cultured hippocampal neurons by CaM-kinase II described elsewhere. This CaM-kinase II regulatory phosphorylation site is conserved in all AMPA/kainate-type Glutamate Receptors, and its phosphorylation may be important in enhancing postsynaptic responsiveness as occurs during synaptic plasticity.