Nitric oxide donors increase PVR/CD155 DNAM-1 ligand expression in multiple myeloma cells: role of DNA damage response activation.

Abstract

BACKGROUND:

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 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.

METHODS:

Six 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).

RESULTS:

Our 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.

CONCLUSIONS:

The 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.

• Authors: Cinzia Fionda, Maria Pia Abruzzese, Alessandra Zingoni, Alessandra Soriani, Biancamaria Ricci, Rosa Molfetta, Rossella Paolini, Angela Santoni, Marco Cippitelli
• Journal: BMC cancer (BMC Cancer) Vol. 15 Pg. 17 (Jan 22 2015) ISSN: 1471-2407 [Electronic] England
• PMID: 25609078 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene
• Antigens, Differentiation, T-Lymphocyte
• CD226 antigen
• Ligands
• NCX 4040
• Nitro Compounds
• Receptors, Virus
• Triazenes
• poliovirus receptor
• Nitric Oxide
• Aspirin

Topics

• Antigens, Differentiation, T-Lymphocyte (biosynthesis, genetics)
• Aspirin (administration & dosage, analogs & derivatives)
• Cell Line, Tumor
• DNA Damage (drug effects, genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Ligands
• Multiple Myeloma (drug therapy, genetics, metabolism)
• Nitric Oxide (metabolism)
• Nitro Compounds (administration & dosage)
• Receptors, Virus (biosynthesis, genetics)
• Triazenes (administration & dosage)