Inhibition of glutamate regulated calcium entry into leukemic megakaryoblasts reduces cell proliferation and supports differentiation
- Kamal, T; Green, TN; Morel-Kopp, MC; Ward, CM; McGregor, AL; McGlashan, SR; Bohlander, SK; Browett, PJ; Teague, L; During, MJ; Skerry, TM; Josefsson, EC; Kalev-Zylinska, ML;
Publication Year 2015-09, Volume 27, Issue #9, Page 1860-1872
- Journal Title
- Cell Signal
- Publication Type
- Journal Article
- Human megakaryocytes release glutamate and express glutamate-gated Ca2+-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 Ca2+ 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 Ca2+ 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 Ca2+ entry into Meg-01 cells, amplified Ca2+ 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; 5-100 muM) were weakly cytotoxic but mainly reduced cell numbers by suppressing proliferation. The use-dependent NMDAR inhibitor, memantine (100 muM), reduced numbers and proliferation of Meg-01 cells to less than 20% of controls (IC50 20 muM and 36 muM, respectively). In the presence of NMDAR inhibitors cells acquired morphologic and immunophenotypic features of megakaryocytic differentiation. In conclusion, NMDARs provide a novel pathway for Ca2+ 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.
- WEHI Research Division(s)
- Cancer And Haematology
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-05-22 11:19:36Last Modified: 2015-07-14 03:19:39