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Glutamate-mediated NMDA Receptor Induces Ca2+ Entry And Increases Growth Of Leukaemic Megakaryoblasts | 29523
ISSN: 1948-5956

Journal of Cancer Science & Therapy
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Glutamate-mediated NMDA receptor induces Ca2+ entry and increases growth of leukaemic megakaryoblasts

5th Asia-Pacific Summit on Cancer Therapy

Tania Kamal

Posters Accepted Abstracts: J Cancer Sci Ther

DOI: 10.4172/1948-5956.S1.048

The discovery of CALR mutations in myeloproliferative neoplasms highlighted importance of Ca2+ homeostasis in megakaryocytic cells. Megakaryocytes express N-methyl-D-aspartate receptors (NMDARs) known to mediate glutamateinduced Ca2+ entry in other cells. However, the roles of glutamate and NMDARs in normal and malignant megakaryocytes are not known. The aim of this study was to determine whether NMDARs provide a novel pathway for Ca2+ entry into leukaemic megakaryoblasts and if so, whether modulating NMDAR activity could influence leukaemia cell growth. Expression of NMDAR subunits was examined in human bone marrow including neoplastic and megakaryoblastic leukaemia cell lines (Meg-01, Set-2 and K-562). Well-established NMDAR modulators (agonists and antagonists) were employed to determine NMDAR effects on the levels of intracellular Ca2+, cell viability, proliferation and differentiation. We found that human leukaemic cells expressed distinct combinations of the NMDAR subunits. Low concentrations of glutamate and NMDAR antagonists (riluzole, memantine, MK-801 and AP5; 5-100 ?M) attenuated cell growth in culture mostly through the inhibition of cell proliferation. The use-dependent NMDAR antagonist, memantine (100 ?M) reduced Meg-01 viability to 1610% of controls (IC50 20 ?M) and inhibited Meg-01 proliferation to 416% (IC50 36 ?M). Further, after three days in the presence of NMDAR antagonists, cells acquired morphologic and immunophenotypic features of megakaryocytic differentiation. Our findings indicate that NMDARs provide a novel pathway for Ca2+ entry into leukaemic megakaryoblasts that supports cell proliferation. NMDAR inhibitors counteract these effects suggesting a novel way to interrupt growth of this type of leukaemia.
Tania Kamal is a PhD student at The University of Auckland, New Zealand.
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