Background: DNAX accessory molecule-1 (DNAM-1) is an activating receptor constitutively expressed by macrophages/\ndendritic cells and by T lymphocytes and Natural Killer (NK) cells, having an important role in anticancer responses; in\nthis regard, combination therapies able to enhance the expression of DNAM-1 ligands on tumor cells are of therapeutic\ninterest. In this study, we investigated the effect of different nitric oxide (NO) donors on the expression of the DNAM-1\nligand Poliovirus Receptor/CD155 (PVR/CD155) in multiple myeloma (MM) cells.\nMethods: Six MM cell lines, SKO-007(J3), U266, OPM-2, RPMI-8226, ARK and LP1 were used to investigate the activity of\ndifferent nitric oxide donors [DETA-NO and the NO-releasing prodrugs NCX4040 (NO-aspirin) and JS-K] on the expression\nof PVR/CD155, using Flow Cytometry and Real-Time PCR. Western-blot and specific inhibitors were employed\nto investigate the role of soluble guanylyl cyclase/cGMP and activation of the DNA damage response (DDR).\nResults: Our results indicate that increased levels of nitric oxide can upregulate PVR/CD155 cell surface and\nmRNA expression in MM cells; in addition, exposure to nitric oxide donors renders myeloma cells more\nefficient to activate NK cell degranulation and enhances their ability to trigger NK cell-mediated cytotoxicity.\nWe found that activation of the soluble guanylyl cyclase and increased cGMP concentrations by nitric oxide is\nnot involved in the up-regulation of ligand expression. On the contrary, treatment of MM cells with nitric oxide\ndonors correlated with the activation of a DNA damage response pathway and inhibition of the ATM /ATR/Chk1/2\nkinase activities by specific inhibitors significantly abrogates up-regulation.\nConclusions: The present study provides evidence that regulation of the PVR/CD155 DNAM-1 ligand expression\nby nitric oxide may represent an additional immune-mediated mechanism and supports the anti-myeloma activity\nof nitric oxide donors.
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