1. Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells.
- Author
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Zingoni A, Cecere F, Vulpis E, Fionda C, Molfetta R, Soriani A, Petrucci MT, Ricciardi MR, Fuerst D, Amendola MG, Mytilineos J, Cerboni C, Paolini R, Cippitelli M, and Santoni A
- Subjects
- ADAM Proteins genetics, ADAM10 Protein, ADP-ribosyl Cyclase 1 genetics, ADP-ribosyl Cyclase 1 immunology, Amyloid Precursor Protein Secretases genetics, Bone Marrow Cells drug effects, Bone Marrow Cells immunology, Bone Marrow Cells pathology, Cell Line, Tumor, Cellular Senescence, DNA Damage, Doxorubicin pharmacology, Histocompatibility Antigens Class I genetics, Humans, Killer Cells, Natural immunology, Killer Cells, Natural pathology, Matrix Metalloproteinase Inhibitors pharmacology, Melphalan pharmacology, Membrane Glycoproteins genetics, Membrane Glycoproteins immunology, Membrane Proteins genetics, Multiple Myeloma genetics, Multiple Myeloma immunology, Multiple Myeloma pathology, NK Cell Lectin-Like Receptor Subfamily K genetics, NK Cell Lectin-Like Receptor Subfamily K immunology, Plasma Cells immunology, Plasma Cells pathology, Primary Cell Culture, Proteolysis, Reactive Oxygen Species immunology, Signal Transduction, Syndecan-1 genetics, Syndecan-1 immunology, ADAM Proteins immunology, Amyloid Precursor Protein Secretases immunology, Cytotoxins pharmacology, Gene Expression Regulation, Neoplastic, Histocompatibility Antigens Class I immunology, Killer Cells, Natural drug effects, Membrane Proteins immunology, Plasma Cells drug effects
- Abstract
Genotoxic stress can promote antitumor NK cell responses by upregulating the surface expression of activating ligands on cancer cells. Moreover, a number of studies suggested a role for soluble NK group 2D ligands in the impairment of NK cell tumor recognition and killing. We investigated whether genotoxic stress could promote the release of NK group 2D ligands (MHC class I-related chain [MIC]A and MICB), as well as the molecular mechanisms underlying this event in human multiple myeloma (MM) cells. Our results show that genotoxic agents used in the therapy of MM (i.e., doxorubicin and melphalan) selectively affect the shedding of MIC molecules that are sensitive to proteolytic cleavage, whereas the release of the short MICA*008 allele, which is frequent in the white population, is not perturbed. In addition, we found that a disintegrin and metalloproteinase 10 expression is upregulated upon chemotherapeutic treatment both in patient-derived CD138(+)/CD38(+) plasma cells and in several MM cell lines, and we demonstrate a crucial role for this sheddase in the proteolytic cleavage of MIC by means of silencing and pharmacological inhibition. Interestingly, the drug-induced upregulation of a disintegrin and metalloproteinase 10 on MM cells is associated with a senescent phenotype and requires generation of reactive oxygen species. Moreover, the combined use of chemotherapeutic drugs and metalloproteinase inhibitors enhances NK cell-mediated recognition of MM cells, preserving MIC molecules on the cell surface and suggesting that targeting of metalloproteinases in conjunction with chemotherapy could be exploited for NK cell-based immunotherapeutic approaches, thus contributing to avoid the escape of malignant cells from stress-elicited immune responses., (Copyright © 2015 by The American Association of Immunologists, Inc.)
- Published
- 2015
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