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

BMC Cancer

Marco Cippitelli¹  Angela Santoni²  Rossella Paolini¹  Rosa Molfetta¹  Biancamaria Ricci¹  Alessandra Soriani¹  Alessandra Zingoni¹  Maria Pia Abruzzese¹  Cinzia Fionda¹ 

[1]Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Viale Regina Elena 291, Rome, 00161, Italy

[2]Istituto Mediterraneo di Neuroscienze Neuromed, Pozzilli, IS, Italy

关键词: Chemoimmunotherapy;    DNA damage response;    Natural killer;    DNAM-1;    Nitric oxide;    Multiple myeloma;   

Others  :  1106713
DOI  :  10.1186/s12885-015-1023-5

 received in 2014-10-01, accepted in 2015-01-14,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Fionda et al.; licensee BioMed Central.

【 图 表 】

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