NMDA receptors are important regulators of pancreatic cancer and are potential targets for treatment

North, William G.; Liu, Fuli; Lin, Liz Z; Tian, Ruiyang; Akerman, Bonnie L.

doi:10.2147/cpaa.s140057

Cited by 20 publications

(25 citation statements)

References 27 publications

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“…Since the GluN2B is widely distributed in the adult brain and has been reported in a range of disorders [ 21 ], this model will potentially be a key target of positive allosteric modulators [ 22 ]. Recently, it has been reported that GluN1 and GluN2B were found to be membrane components of all invasive adenocarcinoma and neuroendocrine pancreatic tumors [ 23 ].…”

Section: Resultsmentioning

confidence: 99%

How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors?

et al. 2018

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NMDA-type glutamate receptors (NMDAR) are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system. NMDAR dysfunction has been found to be involved in various neurological disorders. Recent crystallographic and EM studies have shown the static structure of different states of the non-human NMDARs. Here we describe a model of a human NMDA receptor (hNMDAR) and its molecular dynamics (MD) before and after the binding of agonist ligands, glutamate and glycine. It is shown that the binding of ligands promotes a global reduction in molecular flexibility that produces a more tightly packed conformation than the unbound hNMDAR, and a higher cooperative regularity of moving. The ligand-induced synchronization of motion, identified on all structural levels of the modular hNMDA receptor is apparently a fundamental factor in channel gating. Although the time scale of the MD simulations (300 ns) was not sufficient to observe the complete gating event, the obtained data has shown the ligand-induced stabilization of hNMDAR that conforms the “going to be open state”. We propose a mechanistic dynamic model of the ligand-dependent gating mechanism in the hNMDA receptor. At the binding of the ligands, the differently twisted conformations of the highly flexible receptor are stabilized in unique conformation with a linear molecular axis, which is a condition that is optimal for pore development. By searching the receptor surface, we have identified three new pockets, which are different from the pockets described in the literature as the potential and known positive allosteric modulator binding sites. A successful docking of two NMDAR modulators to their binding sites validates the model of a human NMDA receptor as a biological relevant target.

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Section: Resultsmentioning

confidence: 99%

How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors?

et al. 2018

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“…Different types of ionotropic receptors including P2XR and NMDAR have been reported to be expressed in PDAC (Kunzli et al, 2007;Hansen et al, 2008;Burnstock and Novak, 2012;Li and Hanahan, 2013;North et al, 2017). Among P2XR, P2X7R is the most well described (Kunzli et al, 2007;Hansen et al, 2008;Burnstock and Novak, 2012).This ionotropic receptor has shown to be overexpressed in PDAC cell lines and tissue (Kunzli et al, 2007;Giannuzzo et al, 2015), and to be implicated in the proliferating, apoptotic, migrating, and invading processes of PDAC (Kunzli et al, 2007;Hansen et al, 2008;Giannuzzo et al, 2015;Giannuzzo et al, 2016;Choi et al, 2018).…”

Section: Ionotropic Receptors In Pdac Purinergic Receptors (P2xr) Andmentioning

confidence: 99%

“…Among P2XR, P2X7R is the most well described (Kunzli et al, 2007;Hansen et al, 2008;Burnstock and Novak, 2012).This ionotropic receptor has shown to be overexpressed in PDAC cell lines and tissue (Kunzli et al, 2007;Giannuzzo et al, 2015), and to be implicated in the proliferating, apoptotic, migrating, and invading processes of PDAC (Kunzli et al, 2007;Hansen et al, 2008;Giannuzzo et al, 2015;Giannuzzo et al, 2016;Choi et al, 2018). In addition, the expression of NMDAR was found in both PDAC cell lines and PDAC tumors, and their inhibition and blocking resulted in reduced different PDAC cell lines viability and survival (Li and Hanahan, 2013;North et al, 2017). Furthermore, an inhibition of NMDAR prevented growth of tumor xenografts (Li and Hanahan, 2013;North et al, 2017).…”

Section: Ionotropic Receptors In Pdac Purinergic Receptors (P2xr) Andmentioning

confidence: 99%

“…In addition, the expression of NMDAR was found in both PDAC cell lines and PDAC tumors, and their inhibition and blocking resulted in reduced different PDAC cell lines viability and survival (Li and Hanahan, 2013;North et al, 2017). Furthermore, an inhibition of NMDAR prevented growth of tumor xenografts (Li and Hanahan, 2013;North et al, 2017).…”

Section: Ionotropic Receptors In Pdac Purinergic Receptors (P2xr) Andmentioning

confidence: 99%

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Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancerrelated deaths in United States and Europe. It is predicted that PDAC will become the second leading cause of cancer-related deaths during the next decades. The development of PDAC is not well understood, however, studies have shown that dysregulated exocrine pancreatic fluid secretion can contribute to pathologies of exocrine pancreas, including PDAC. The major roles of healthy exocrine pancreatic tissue are secretion of enzymes and bicarbonate rich fluid, where ion channels participate to fine-tune these biological processes. It is well known that ion channels located in the plasma membrane regulate multiple cellular functions and are involved in the communication between extracellular events and intracellular signaling pathways and can function as signal transducers themselves. Hereby, they contribute to maintain resting membrane potential, electrical signaling in excitable cells, and ion homeostasis. Despite their contribution to basic cellular processes, ion channels are also involved in the malignant transformation from a normal to a malignant phenotype. Aberrant expression and activity of ion channels have an impact on essentially all hallmarks of cancer defined as; uncontrolled proliferation, evasion of apoptosis, sustained angiogenesis and promotion of invasion and migration. Research indicates that certain ion channels are involved in the aberrant tumor growth and metastatic processes of PDAC. The purpose of this review is to summarize the important expression, localization, and function of ion channels in normal exocrine pancreatic tissue and how they are involved in PDAC progression and development. As ion channels are suggested to be potential targets of treatment they are furthermore suggested to be biomarkers of different cancers. Therefore, we describe the importance of ion channels in PDAC as markers of diagnosis and clinical factors.

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“…In previous studies, ifenprodil showed an inhibitory effect on human esophageal cancer cell lines via NMDA receptor-mediated apoptosis [42]. There are also previous studies that NMDA receptor antagonists including ifenprodil have been tested in vitro and in vivo for ovarian cancer [43] and pancreatic cancer [44]. Ifenprodil has been reported more effective compared to other NMDA inhibitors within the well below doses known to have significant behavioral effects in rodents [44].…”

Section: Resultsmentioning

confidence: 99%

Discovery of therapeutic agents for prostate cancer using genome-scale metabolic modeling and drug repositioning

et al. 2019

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Background: Genome-scale metabolic models (GEMs) offer insights into cancer metabolism and have been used to identify potential biomarkers and drug targets. Drug repositioning is a time-and cost-effective method of drug discovery that can be applied together with GEMs for effective cancer treatment. Methods: In this study, we reconstruct a prostate cancer (PRAD)-specific GEM for exploring prostate cancer metabolism and also repurposing new therapeutic agents that can be used in development of effective cancer treatment. We integrate global gene expression profiling of cell lines with N1000 different drugs through the use of prostate cancer GEM and predict possible drug-gene interactions. Findings: We identify the key reactions with altered fluxes based on the gene expression changes and predict the potential drug effect in prostate cancer treatment. We find that sulfamethoxypyridazine, azlocillin, hydroflumethiazide, and ifenprodil can be repurposed for the treatment of prostate cancer based on an in silico cell viability assay. Finally, we validate the effect of ifenprodil using an in vitro cell assay and show its inhibitory effect on a prostate cancer cell line. Interpretation: Our approach demonstate how GEMs can be used to predict therapeutic agents for cancer treatment based on drug repositioning. Besides, it paved a way and shed a light on the applicability of computational models to real-world biomedical or pharmaceutical problems.

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NMDA receptors are important regulators of pancreatic cancer and are potential targets for treatment

Cited by 20 publications

References 27 publications

How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors?

How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors?

Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma

Discovery of therapeutic agents for prostate cancer using genome-scale metabolic modeling and drug repositioning

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