6-cyano-7-nitroquinoxaline-2-3-dione and Leukemia--T-Cell

Glutamate is the major excitatory neurotransmitter of the nervous system. We previously found that glutamate activates normal human T-cells, inducing their adhesion and chemotaxis, via its glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype 3 (GluR3) expressed in these cells. Here, we discovered that human T-leukemia (Jurkat) and cutaneous sezary T-lymphoma (HuT-78) cells also express high levels of GluR3. Furthermore, glutamate (10 nM) elevates CD147/EMMPRIN, a cancer-associated matrix metalloproteinases (MMPs) inducer, promoting spread of many tumors. Glutamate-induced CD147 elevation in both cancerous and normal human T-cells was mimicked by AMPA (glutamate/AMPA-receptor agonist) and blocked by CNQX (glutamate/AMPA-receptor antagonist). Importantly, glutamate also increased gelatinase MMP-9 secretion by T-lymphoma. Finally, ex vivo pre-treatment of T-leukemia with glutamate enhanced their subsequent in vivo engraftment into chick embryo liver and chorioallantoic membrane. Together, these findings reveal that glutamate elevates cancer associated proteins and activity in T-cell cancers and by doing so may facilitate their growth and spread, especially to and within the nervous system. If so, glutamate receptors in T-cell malignancies should be blocked.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Basigin; Cell Line, Tumor; Cells, Cultured; Chick Embryo; Chorioallantoic Membrane; Dose-Response Relationship, Drug; Flow Cytometry; Fluorescent Antibody Technique; Glutamic Acid; Graft Survival; Green Fluorescent Proteins; Humans; Jurkat Cells; Leukemia, T-Cell; Matrix Metalloproteinase 9; Neoplasm Transplantation; Polymerase Chain Reaction; Receptors, AMPA; Transplantation, Heterologous