Abstract
BackgroundDNAX accessory molecule-1 (DNAM-1) is an activating receptor constitutively expressed by macrophages/dendritic cells and by T lymphocytes and Natural Killer (NK) cells, having an important role in anticancer responses; in this regard, combination therapies able to enhance the expression of DNAM-1 ligands on tumor cells are of therapeutic interest. In this study, we investigated the effect of different nitric oxide (NO) donors on the expression of the DNAM-1 ligand Poliovirus Receptor/CD155 (PVR/CD155) in multiple myeloma (MM) cells.MethodsSix MM cell lines, SKO-007(J3), U266, OPM-2, RPMI-8226, ARK and LP1 were used to investigate the activity of different nitric oxide donors [DETA-NO and the NO-releasing prodrugs NCX4040 (NO-aspirin) and JS-K] on the expression of PVR/CD155, using Flow Cytometry and Real-Time PCR. Western-blot and specific inhibitors were employed to investigate the role of soluble guanylyl cyclase/cGMP and activation of the DNA damage response (DDR).ResultsOur results indicate that increased levels of nitric oxide can upregulate PVR/CD155 cell surface and mRNA expression in MM cells; in addition, exposure to nitric oxide donors renders myeloma cells more efficient to activate NK cell degranulation and enhances their ability to trigger NK cell-mediated cytotoxicity. We found that activation of the soluble guanylyl cyclase and increased cGMP concentrations by nitric oxide is not involved in the up-regulation of ligand expression. On the contrary, treatment of MM cells with nitric oxide donors correlated with the activation of a DNA damage response pathway and inhibition of the ATM /ATR/Chk1/2 kinase activities by specific inhibitors significantly abrogates up-regulation.ConclusionsThe present study provides evidence that regulation of the PVR/CD155 DNAM-1 ligand expression by nitric oxide may represent an additional immune-mediated mechanism and supports the anti-myeloma activity of nitric oxide donors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1023-5) contains supplementary material, which is available to authorized users.
Highlights
DNAX accessory molecule-1 (DNAM-1) is an activating receptor constitutively expressed by macrophages/ dendritic cells and by T lymphocytes and Natural Killer (NK) cells, having an important role in anticancer responses; in this regard, combination therapies able to enhance the expression of DNAM-1 ligands on tumor cells are of therapeutic interest
Our results indicate that increased levels of nitric oxide (NO) can enhance surface expression of Poliovirus receptor-CD155 (PVR)/CD155 on MM cell lines, rendering these cells more susceptible to NK cell mediated killing via DNAM-1 recognition
Nitric oxide upregulates expression of DNAM-1 ligand PVR/CD155 on human multiple myeloma cells In order to characterize novel agents and molecular pathways able to regulate the expression of NK cell activating ligands in MM cells, we investigated the activity of nitric oxide donors [DETA-NO and the NO-releasing pro-drugs NCX4040 (NO-aspirin) and JS-K] on the expression of the CD155/PVR, an activating DNAM-1 ligand regulated by DNA damage response (DDR) and reactive radicals in different models [23,24]
Summary
DNAX accessory molecule-1 (DNAM-1) is an activating receptor constitutively expressed by macrophages/ dendritic cells and by T lymphocytes and Natural Killer (NK) cells, having an important role in anticancer responses; in this regard, combination therapies able to enhance the expression of DNAM-1 ligands on tumor cells are of therapeutic interest. In the past decade, the use of autologous hematopoietic stem cell transplantation (HSCT) and the Increasing evidence in myeloma patients has shown that Natural Killer (NK) cells can elicit potent allogeneic and autologous responses to myeloma cells, strongly supporting their anti-tumor potential in response to immunomodulatory drugs or following allogeneic stem cell transplantation [6,7,8] In this regard, several studies have shown that triggering of different activating receptors, such as DNAX accessory molecule-1 (DNAM-1), NK group 2D (NKG2D) and Natural Cytotoxicity Receptors (NCRs), is involved in the recognition and killing of MM. NO may play different roles in regulating cancer microenvironment and progression, which can be cell-type and context specific
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