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.

Nitric oxide donors increase PVR/CD155 DNAM-1 ligand expression in multiple myeloma cells: role of DNA damage response activation / Fionda, Cinzia; Abruzzese, MARIA PIA; Zingoni, Alessandra; Soriani, Alessandra; Ricci, Biancamaria; Molfetta, Rosa; Paolini, Rossella; Santoni, Angela; Cippitelli, Marco. - In: BMC CANCER. - ISSN 1471-2407. - ELETTRONICO. - 15:(2015), pp. 1-14. [10.1186/s12885-015-1023-5]

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

FIONDA, Cinzia;ABRUZZESE, MARIA PIA;ZINGONI, Alessandra;SORIANI, Alessandra;RICCI, BIANCAMARIA;MOLFETTA, Rosa;PAOLINI, Rossella;SANTONI, Angela;CIPPITELLI, Marco
2015

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.
2015
Aspirin; Cell Line, Tumor; DNA Damage; Gene Expression Regulation, Neoplastic; Humans; Ligands; Multiple Myeloma; Nitric Oxide; Nitro Compounds;
01 Pubblicazione su rivista::01a Articolo in rivista
Nitric oxide donors increase PVR/CD155 DNAM-1 ligand expression in multiple myeloma cells: role of DNA damage response activation / Fionda, Cinzia; Abruzzese, MARIA PIA; Zingoni, Alessandra; Soriani, Alessandra; Ricci, Biancamaria; Molfetta, Rosa; Paolini, Rossella; Santoni, Angela; Cippitelli, Marco. - In: BMC CANCER. - ISSN 1471-2407. - ELETTRONICO. - 15:(2015), pp. 1-14. [10.1186/s12885-015-1023-5]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/870926
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