dc.contributor.author |
Kamal, Tania |
en |
dc.contributor.author |
Green, Taryn |
en |
dc.contributor.author |
Morel-Kopp, M-C |
en |
dc.contributor.author |
Ward, CM |
en |
dc.contributor.author |
McGregor, Ailsa |
en |
dc.contributor.author |
McGlashan, Susan |
en |
dc.contributor.author |
Bohlander, Stefan |
en |
dc.contributor.author |
Browett, Peter |
en |
dc.contributor.author |
Teague, L |
en |
dc.contributor.author |
During, MJ |
en |
dc.contributor.author |
Skerry, TM |
en |
dc.contributor.author |
Josefsson, EC |
en |
dc.contributor.author |
Kalev, Maggie |
en |
dc.date.accessioned |
2017-07-03T02:49:47Z |
en |
dc.date.issued |
2015-09 |
en |
dc.identifier.citation |
Cellular Signalling 27(9):1860-1872 Sep 2015 |
en |
dc.identifier.issn |
0898-6568 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/33947 |
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 |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
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 |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
487455 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Anatomy and Medical Imaging |
en |
pubs.org-id |
Molecular Medicine |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
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 |