Increasing evidence indicate that stimulation of the host immune response represents a promising therapeutic approach against cancer. Multiple Myeloma (MM) is a debilitating malignancy in which abnormal plasma cells (PCs) accumulate in the bone marrow, and a number of evidence showed that MM cells are potential targets of Natural Killer (NK) cell killing. The expression of NK cell activating DNAM-1 and NKG2D ligands on multiple myeloma cells has been described, and although the regulation of NKG2D ligands is not completely understood, increasing evidence demonstrate that cellular stress and induction of DNA damage response can up-regulate their expression. Little information is available about the mechanisms controlling DNAM-1 ligand regulation. In this study, we show that myeloma cells treated with low doses of therapeutic agents commonly used in the management of patients with MM, such as doxorubicin, melphalan, and bortezomib, up-regulate DNAM-1 and NKG2D ligands. Accordingly, therapeutic drug treatment of MM cells increases NK-cell degranulation, being the NKG2D and DNAM-1 receptors the major triggering molecules. Similar data were also obtained using ex vivo primary PCs derived from MM patients. We demonstrated that drug-induced NKG2D and DNAM-1 ligand up-regulation was triggered by the DNA damage response pathway and, in particular, ATM/ATR and Chk1/2 have a key role. By contrast, p53 phosphorylation is induced by chemotherapeutic treatments but is not involved in ligand up-regulation. We showed that low doses of genotoxic agents lead MM cells to enter in a premature senescence, characterized by a G2M phase-arrested cell cycle, and that NKG2D and DNAM-1 ligand up-regulation occurs preferentially on senescent cells. Moreover, our experiments demonstrated a role for the Reactive Oxygen Species (ROS) in drug-induced DNA damage response activation and subsequent ligand up-regulation and senescent phenotype. Altogether, our findings have identified a common pathway that can trigger the up-regulation of different NK cell-activating ligands and suggest that NK cells represent an immunosurveillance mechanism toward cells undergoing stress-induced senescent programs.

Role of redox-activated DNA damage response in the regulation of drug-induced NKG2D and DNAM-1 ligand expression on human senescent multiple myeloma cells / Iannitto, MARIA LUISA. - (2012 Mar 27).

Role of redox-activated DNA damage response in the regulation of drug-induced NKG2D and DNAM-1 ligand expression on human senescent multiple myeloma cells

IANNITTO, MARIA LUISA
27/03/2012

Abstract

Increasing evidence indicate that stimulation of the host immune response represents a promising therapeutic approach against cancer. Multiple Myeloma (MM) is a debilitating malignancy in which abnormal plasma cells (PCs) accumulate in the bone marrow, and a number of evidence showed that MM cells are potential targets of Natural Killer (NK) cell killing. The expression of NK cell activating DNAM-1 and NKG2D ligands on multiple myeloma cells has been described, and although the regulation of NKG2D ligands is not completely understood, increasing evidence demonstrate that cellular stress and induction of DNA damage response can up-regulate their expression. Little information is available about the mechanisms controlling DNAM-1 ligand regulation. In this study, we show that myeloma cells treated with low doses of therapeutic agents commonly used in the management of patients with MM, such as doxorubicin, melphalan, and bortezomib, up-regulate DNAM-1 and NKG2D ligands. Accordingly, therapeutic drug treatment of MM cells increases NK-cell degranulation, being the NKG2D and DNAM-1 receptors the major triggering molecules. Similar data were also obtained using ex vivo primary PCs derived from MM patients. We demonstrated that drug-induced NKG2D and DNAM-1 ligand up-regulation was triggered by the DNA damage response pathway and, in particular, ATM/ATR and Chk1/2 have a key role. By contrast, p53 phosphorylation is induced by chemotherapeutic treatments but is not involved in ligand up-regulation. We showed that low doses of genotoxic agents lead MM cells to enter in a premature senescence, characterized by a G2M phase-arrested cell cycle, and that NKG2D and DNAM-1 ligand up-regulation occurs preferentially on senescent cells. Moreover, our experiments demonstrated a role for the Reactive Oxygen Species (ROS) in drug-induced DNA damage response activation and subsequent ligand up-regulation and senescent phenotype. Altogether, our findings have identified a common pathway that can trigger the up-regulation of different NK cell-activating ligands and suggest that NK cells represent an immunosurveillance mechanism toward cells undergoing stress-induced senescent programs.
27-mar-2012
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/918651
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