Chemotherapy-Induced Activation of ADAM-17: A Novel Mechanism of Drug Resistance in Colorectal Cancer

Kyula, Joan; Schaeybroeck, Sandra Van; Doherty, Joanne; Fenning, Catherine; Longley, Daniel B.; Johnston, Patrick G.

doi:10.1158/1078-0432.ccr-10-0014

Cited by 87 publications

(93 citation statements)

References 35 publications

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“…These discrepancies may depend on the different cellular systems and/or experimental conditions used. Our evidence for ROS involvement in ADAM10 upregulation and MICB shedding are in line with the notion that conditions causing cellular stress, including ionizing radiation, chemotherapeutic agents, or ROS, can lead to increased metalloproteinase-mediated release of cell surface molecules (49)(50)(51) and suggest that stress stimuli promote the proteolytic process by upregulating metalloproteinase expression and activity. We also are the first to describe, to our knowledge, that genotoxic stress-induced upregulation of ADAM10 expression and sMICB secretion are primarily associated with senescent cells.…”

Section: Discussionsupporting

confidence: 87%

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: Discussionsupporting

confidence: 87%

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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“…ADAM17 activity is also increased on cellular treatment with chemotherapeutic agents (40,41) and ADAM17 activation by the antimetabolite 5-FU and the topoisomerase I inhibitor SN-38 primarily occurs in a Kras-mutated background and via the MAP/ERK kinase pathway. Our results demonstrate that irradiation promotes ADAM17 activation, but in a furinmediated way and interestingly, in both Kras-wild-type (NCI-H125, CALU-3) and Kras-mutated NSCLC cell lines (A549, H460).…”

Section: Discussionmentioning

confidence: 99%

Secretome Signature Identifies ADAM17 as Novel Target for Radiosensitization of Non–Small Cell Lung Cancer

Sharma

Bender

Zimmermann

et al. 2016

Clinical Cancer Research

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Purpose: Ionizing radiation (IR) induces intracellular signaling processes as part of a treatment-induced stress response. Here we investigate IR-induced ADAM17 activation and the role of ADAM17-shed factors for radiation resistance in non-small cell lung cancer.Experimental Design: Large-scale secretome profiling was performed using antibody arrays. Secretion kinetics of ADAM17 substrates was determined using ELISA across multiple in vitro and in vivo models of non-small cell lung cancer. Clonogenic survival and tumor xenograft assays were performed to determine radiosensitization by ADAM17 inhibition.Results: On the basis of a large-scale secretome screening, we investigated secretion of auto-or paracrine factors in non-small cell lung cancer in response to irradiation and discovered the ADAM17 network as a crucial mediator of resistance to IR. Irradiation induced a dose-dependent increase of furin-mediated cleavage of the ADAM17 proform to active ADAM17, which resulted in enhanced ADAM17 activity in vitro and in vivo. Genetic or pharmacologic targeting of ADAM17 suppressed IR-induced shedding of secreted factors, downregulated ErbB signaling in otherwise cetuximab-resistant target cells, and enhanced IRinduced cytotoxicity. The combined treatment modality of IR with the ADAM17 inhibitor TMI-005 resulted in a supra-additive antitumor response in vivo demonstrating the potential of ADAM17 targeting in combination with radiotherapy.Conclusions: Radiotherapy activates ADAM17 in non-small cell lung cancer, which results in shedding of multiple survival factors, growth factor pathway activation, and IR-induced treatment resistance. We provide a sound rationale for repositioning ADAM17 inhibitors as short-term adjuvants to improve the radiotherapy outcome of non-small cell lung cancer. Clin Cancer Res; 22(17); 4428-39. Ó2016 AACR.

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“…Accumulating evidence suggests that ADAMs are also important in cell survival (18,19). Certain members of the ADAM family, including ADAM9, ADAM10 and ADAM17, are closely involved in tumorigenesis, and the development and metastasis of tumors (13,20,21).…”

Section: Discussionmentioning

confidence: 99%

Silencing ADAM10 inhibits the in vitro and in vivo growth of hepatocellular carcinoma cancer cells

Liu

Zhang

et al. 2014

Molecular Medicine Reports

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Abstract.A disintegrin and metalloprotease 10 (ADAM10) is a transmembrane protein associated with metastasis in a number of types of cancer. Little is known, however, regarding the role of ADAM10 in hepatocellular carcinoma (HCC). The aim of the present study was to evaluate whether downregulation of ADAM10 effects HCC cell proliferation, cell cycle, cell migration and cell invasion. A recombinant small hairpin RNA expression vector carrying ADAM10 was constructed and then transfected into the HepG2 human HCC cell line. In vitro cell proliferation, cell cycle, cell migration and cell invasion, and in vivo tumor growth were determined following the downregulation of ADAM10 by RNA interference. The results revealed that downregulation of ADAM10 expression in HepG2 tumor cells using the RNA silencing approach significantly suppressed cell proliferation, cell migration and cell invasion in vitro, and tumor growth in vivo. Furthermore, ADAM10 silencing was able to significantly reduce constitutive phosphorylation of phosphoinositide 3-kinase (PI3K) and Akt, which implies that ADAM10 is, at least partially, involved in the activation of the PI3K/Akt signaling pathway. These results suggest that ADAM10 is important in regulating the proliferation and metastasis of HCC. Thus, ADAM10 is a promising therapeutic target for the prevention of tumor metastases in HCC.

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Chemotherapy-Induced Activation of ADAM-17: A Novel Mechanism of Drug Resistance in Colorectal Cancer

Cited by 87 publications

References 35 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

Secretome Signature Identifies ADAM17 as Novel Target for Radiosensitization of Non–Small Cell Lung Cancer

Silencing ADAM10 inhibits the in vitro and in vivo growth of hepatocellular carcinoma cancer cells

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