Reactive Oxygen Species– and DNA Damage Response–Dependent NK Cell Activating Ligand Upregulation Occurs at Transcriptional Levels and Requires the Transcriptional Factor E2F1

Soriani, Alessandra; Iannitto, Maria Luisa; Ricci, Biancamaria; Fionda, Cinzia; Malgarini, Giulia; Morrone, Stefania; Peruzzi, Giovanna; Ricciardi, Maria Rosaria; Petrucci, Maria Teresa; Cippitelli, Marco; Santoni, Angela

doi:10.4049/jimmunol.1400271

Cited by 84 publications

(105 citation statements)

References 63 publications

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“…In addition, our recent data show that drug-induced NKG2DLs are preferentially expressed on senescent MM cells (22), and their expression requires DNA damage response activation and ROS signaling (26).…”

Section: Drug-induced Adam10 Upregulation Is Dependent On Ros Generatmentioning

confidence: 99%

“…To this end, SKO-007(J3) MM cells were treated with DOX for 72 h and then incubated with the fluorogenic substrate C 12 FDG to measure bGal activity, which is a marker of senescence; subsequently, bGal high and bGal low cells were sorted, as previously described (26). Generally, the percentage of drug-induced senescent SKO-007(J3) cells was ∼60% (22, 26) (data not shown).…”

Section: Drug-induced Adam10 Upregulation Is Dependent On Ros Generatmentioning

confidence: 99%

“…DOX and MEL doses used to treat the different cell lines were determined as previously described (22) and corresponded to sublethal doses 10 times lower than the IC 50 values: DOX: ARK (0.06 mM), LP-1 (0.06 mM), OPM-2 (0.08 mM), RPMI-8226 (0.05 mM), SKO-007(J3) (0.05 mM), and U266 (0.1 mM); MEL: ARK (7 mM), LP-1 (21.5 mM), OPM-2 (1.6 mM), RPMI-8226 (1.5 mM), SKO-007(J3) (22 mM), and U266 (15 mM). In some experiments, cells were incubated with 10 mM NAC for 1 h before the drug treatment, as previously described (26). Patient-derived PCs were incubated with MEL (10 mM) or DOX (0.05 mM) for 48-72 h at 37˚C and 5% CO 2 .…”

Section: Drug Treatmentmentioning

confidence: 99%

“…We performed a senescence-associated b-galactosidase (bGal) assay, using the fluorogenic substrate C 12 FDG (Invitrogen), to measure bGal activity by flow cytometry, as previously described (26). Surface staining of ADAM10 was performed on SKO-007(J3) cells or on ex vivo primary PCs, as previously described, and the C 12 -fluorescein signal was measured on the FL-1 detector.…”

Section: Analysis and Isolation Of Senescent Cellsmentioning

confidence: 99%

“…Importantly, drug-induced expression of these ligands on MM cells was always associated with their ability to trigger increased NK cell degranulation in an NKG2D-dependent manner. Our previous findings indicate that upregulation of NKG2DL expression on MM cells in response to genotoxic drugs depends on DNA damage response activation and reactive oxygen species (ROS) signaling and is associated with the induction of a drug-induced senescent phenotype (22,26).…”

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confidence: 99%

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Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Zingoni

Cecere

Vulpis

et al. 2015

The Journal of Immunology

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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

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Section: Drug-induced Adam10 Upregulation Is Dependent On Ros Generatmentioning

confidence: 99%

Section: Drug-induced Adam10 Upregulation Is Dependent On Ros Generatmentioning

confidence: 99%

Section: Drug Treatmentmentioning

confidence: 99%

Section: Analysis and Isolation Of Senescent Cellsmentioning

confidence: 99%

mentioning

confidence: 99%

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Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Zingoni

Cecere

Vulpis

et al. 2015

The Journal of Immunology

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Recognition by natural killer cells of N6‐isopentenyladenosine‐treated human glioma cell lines

Ciaglia

Laezza

Abate

et al. 2017

Intl Journal of Cancer

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Cancer cell stress induced by cytotoxic agents promotes antitumor immune response. Here, we observed that N6-isopentenyladenosine (iPA), an isoprenoid modified adenosine with a well established anticancer activity, was able to induce a significant upregulation of cell surface expression of natural killer (NK) cell activating receptor NK Group 2 member D (NKG2D) ligands on glioma cells in vitro and xenografted in vivo. Specifically suboptimal doses of iPA (0.1 and 1 mM) control the selective upregulation of UL16-binding protein 2 on p53wt-expressing U343MG and that of MICA/B on p53mut-expressing U251MG cells. This event made the glioblastoma cells a potent target for NK cell-mediated recognition through a NKG2D restricted mechanism. p53 siRNA-mediated knock-down and pharmacological inhibition (pifithrin-a), profoundly prevented the iPA action in restoring the immunogenicity of U343MG cells through a mechanism that is dependent upon p53 status of malignancy. Furthermore, accordingly to the preferential recognition of senescent cells by NK cells, we found that iPA treatment was critical for glioma cells entry in premature senescence through the induction of S and G2/M phase arrest. Collectively, our results indicate that behind the well established cytotoxic and antiangiogenic effects, iPA can also display an immune-mediated antitumor activity. The indirect engagement of the innate immune system and its additional activity in primary derived patient's glioma cell model (GBM17 and GBM37), fully increase its translational relevance and led to the exploitation of the isoprenoid pathway for a valid therapeutic intervention in antiglioma research.

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Senescent cells: Living or dying is a matter of NK cells

Antonangeli

Zingoni

Soriani

et al. 2019

Journal of Leukocyte Biology

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NK cells are lymphocytes of the innate immune system, which are able to deal promptly with stressed cells. Cellular senescence is a cell stress response leading to cell cycle arrest that plays a key role during tissue homeostasis and carcinogenesis. In this review, how senescent cells trigger an immune response and, in particular, the ability of NK cells to recognize and clear senescent cells are discussed. Special attention is given to the NK cell‐mediated clearance of senescent tumor cells. NK cells kill senescent cells through a mechanism involving perforin‐ and granzyme‐containing granule exocytosis, and produce IFN‐γ following senescent cell interaction, leading to hypothesize that NK cell‐mediated immune clearance of senescent cells not only relies on direct killing but also on cytokine production, that in turn can promote macrophage activation. These aspects, as well as the ability of the senescence‐associated secretory phenotype and senescent cell‐produced extracellular vesicles to modulate NK cell effector functions, are described.

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Reactive Oxygen Species– and DNA Damage Response–Dependent NK Cell Activating Ligand Upregulation Occurs at Transcriptional Levels and Requires the Transcriptional Factor E2F1

Cited by 84 publications

References 63 publications

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Recognition by natural killer cells of N6‐isopentenyladenosine‐treated human glioma cell lines

Senescent cells: Living or dying is a matter of NK cells

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