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

Pathophysiological Significance of Store-Operated Calcium Entry in Megakaryocyte Function: Opening New Paths for Understanding the Role of Calcium in Thrombopoiesis

“…In the light of the previous demonstration that human mature megakaryocytes display a significant increase in [Ca 2+ ] i upon collagen stimulation [180], these findings support the involvement of SOCE in regulating megakaryocyte interaction with the bone marrow microenvironment, that in turn support proliferation and platelet production [137]. Interestingly, Ca 2+ entry in megakaryocytes in response to ADP can be amplified by glutamate-induced activation of ionotropic N -methyl- d -aspartate receptors (NMDARs), resulting in increased cell proliferation, rather than differentiation, while NMDAR antagonists reduce cell growth and promote differentiation of leukemic megakaryoblasts [181]. …”

N‐methyl‐d‐aspartate receptor mediated calcium influx supports in vitro differentiation of normal mouse megakaryocytes but proliferation of leukemic cell lines

“…Cell lines were grown in supplemented RPMI‐1640, as before 33. To induce differentiation, cells were seeded in 6‐well plates at 2 × 10 5 cells per well and cultured in the presence of phorbol‐12‐myristate‐13‐acetate (PMA; 10 or 25 nmol L −1 ) for 3 days34 or valproic acid (VPA; 500 μmol L −1 ) for 7 days35 (both from Sigma‐Aldrich, Saint Louis, MO).…”

“…32 Although NMDARs have been best characterized in neurons, their functions in non-neuronal cells are being increasingly recognized, including in megakaryocytes. 30,31,33 Previous findings on the NMDAR function in megakaryocytic cells have been somewhat conflicting; both pro- 30,31 and anti- 33 differentiating effects have been shown in different cell types.…”

Physiological Roles of Non-Neuronal NMDA Receptors

“…GRIN2A and GRIN2B hypermethylation inversely correlated with GluN2A and GluN2B expression levels, and was associated with increased cancer cell proliferation and colony formation in vitro [143,144]. In [129,198] Small-cell GluN1; GluN2A-C [134] Connective tissue (muscle, bone) Sarcoma GluN1; GluN2A-D; GluN3A,B [198] Thyroid Carcinoma GluN1; GluN2B-D; GluN3A,B [198] Plasma cell Multiple myeloma GluN1; GluN2A-D [198] Colon/rectum Adenocarcinoma GluN1; GluN2A-D; GluN3A [129,138,198,199] T cell Leukemia GluN2A-D; GluN3A [198] Breast Adenocarcinoma GluN1; GluN2A-D; GluN3A [126,129,198] Ovaries Cystadenocarcinoma GluN1; GluN2B [202] Endometrioid adenocarcinoma GluN1; GluN2B [202] Clear-cell carcinoma GluN1; GluN2B [202] Megakaryoblasts Leukemic megarkaryoblasts GluN1; GluN2A-D; GluN3A,B [132] Oral cavity Squamous cell carcinoma GluN1 [140,141] Larynx Squamous cell carcinoma GluN1; GluN2A-D; GluN3A [136] Bone Osteosarcoma GluN1; GluN2A,B,D; GluN3A [203] accordance, ectopic GluN2B overexpression induced NMDAR-mediated apoptosis in gastric [144] and esophageal squamous cell carcinoma cells [143], and GluN2A overexpression stimulated colorectal cancer cell death [146]. In addition, whole-exome sequencing in malignant melanoma tumor samples revealed a significant prevalence of clustered mutations within GRIN2A functional domains, leading to truncated GluN2A [147], reduced NMDAR complex formation, and increased cancer cell growth, migration [148], and disease progression [149].…”

“…Clinically, serum glutamate positively correlates with cancer progression and invasiveness [128], and the protumor effects of glutamate appear to be largely mediated by NMDARs. NMDARs have been identified in a wide variety of tumor types and cancer cell lines (Table 2), and, regardless of subunit configuration, NMDAR blockade reduces both cancer cell proliferation and invasiveness across many different cancers [129][130][131][132][133][134][135][136][137]. While the precise mechanisms underpinning the NMDAR-mediated effects on proliferation are poorly understood, there are clues.…”