Inhibition of glutamate regulated calcium entry into leukemic megakaryoblasts reduces cell proliferation and supports differentiation

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Show simple item record Kamal, Tania en Green, Taryn en Morel-Kopp, M-C en Ward, CM en McGregor, Ailsa en McGlashan, Susan en Bohlander, Stefan en Browett, Peter en Teague, L en During, MJ en Skerry, TM en Josefsson, EC en Kalev, Maggie en 2017-07-03T02:49:47Z en 2015-09 en
dc.identifier.citation Cellular Signalling 27(9):1860-1872 Sep 2015 en
dc.identifier.issn 0898-6568 en
dc.identifier.uri en
dc.description.abstract Human megakaryocytes release glutamate and express glutamate-gated Ca(2+)-permeable N-methyl-D-aspartate receptors (NMDARs) that support megakaryocytic maturation. While deregulated glutamate pathways impact oncogenicity in some cancers, the role of glutamate and NMDARs in megakaryocytic malignancies remains unknown. The aim of this study was to determine if NMDARs participate in Ca(2+) responses in leukemic megakaryoblasts and if so, whether modulating NMDAR activity could influence cell growth. Three human cell lines, Meg-01, Set-2 and K-562 were used as models of leukemic megakaryoblasts. NMDAR components were examined in leukemic cells and human bone marrow, including in megakaryocytic disease. Well-established NMDAR modulators (agonists and antagonists) were employed to determine NMDAR effects on Ca(2+) flux, cell viability, proliferation and differentiation. Leukemic megakaryoblasts contained combinations of NMDAR subunits that differed from normal bone marrow and the brain. NMDAR agonists facilitated Ca(2+) entry into Meg-01 cells, amplified Ca(2+) responses to adenosine diphosphate (ADP) and promoted growth of Meg-01, Set-2 and K-562 cells. Low concentrations of NMDAR inhibitors (riluzole, memantine, MK-801 and AP5; 5-100μM) were weakly cytotoxic but mainly reduced cell numbers by suppressing proliferation. The use-dependent NMDAR inhibitor, memantine (100μM), reduced numbers and proliferation of Meg-01 cells to less than 20% of controls (IC50 20μM and 36μM, respectively). In the presence of NMDAR inhibitors cells acquired morphologic and immunophenotypic features of megakaryocytic differentiation. In conclusion, NMDARs provide a novel pathway for Ca(2+) entry into leukemic megakaryoblasts that supports cell proliferation but not differentiation. NMDAR inhibitors counteract these effects, suggesting a novel opportunity to modulate growth of leukemic megakaryoblasts. en
dc.format.medium Print-Electronic en
dc.language eng en
dc.publisher Elsevier BV en
dc.relation.ispartofseries Cellular Signalling en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri en
dc.subject K562 Cells en
dc.subject Humans en
dc.subject Calcium en
dc.subject Glutamic Acid en
dc.subject Receptors, N-Methyl-D-Aspartate en
dc.subject Cell Differentiation en
dc.subject Cell Proliferation en
dc.subject Calcium Signaling en
dc.subject Female en
dc.subject Male en
dc.subject Leukemia, Megakaryoblastic, Acute en
dc.title Inhibition of glutamate regulated calcium entry into leukemic megakaryoblasts reduces cell proliferation and supports differentiation en
dc.type Journal Article en
dc.identifier.doi 10.1016/j.cellsig.2015.05.004 en
pubs.issue 9 en
pubs.begin-page 1860 en
pubs.volume 27 en
dc.rights.holder Copyright: Elsevier BV en
dc.identifier.pmid 25982509 en
pubs.end-page 1872 en
dc.rights.accessrights en
pubs.subtype Article en
pubs.elements-id 487455 en Medical and Health Sciences en Medical Sciences en Anatomy and Medical Imaging en Molecular Medicine en Science en Science Research en Maurice Wilkins Centre (2010-2014) en
dc.identifier.eissn 1873-3913 en
pubs.record-created-at-source-date 2017-07-03 en
pubs.dimensions-id 25982509 en

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