ArticleNeuro-oncology2015
The metalloprotease-disintegrin ADAM8 contributes to temozolomide chemoresistance and enhanced invasiveness of human glioblastoma cells.
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Article in Neuro-oncology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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39citing papers in PubMed
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39 citing papers in PubMed, 58 citations in OpenAlex.
- The role of ADAM8 in intrahepatic cholangiocarcinoma.Discover oncology · 2025Review
- The long non-coding RNA NEAT1 contributes to aberrant STAT3 signaling in pancreatic cancer and is regulated by a metalloprotease-disintegrin ADAM8/miR-181a-5p axis.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- RNA Sequencing Identifies Novel Signaling Pathways and Potential Drug Target Genes Induced by FOSL1 in Glioma Progression and Stemness.Biologics : targets & therapy · 2025Article
- IL-18, a therapeutic target for immunotherapy boosting, promotes temozolomide chemoresistance via the PI3K/AKT pathway in glioma.Journal of translational medicine · 2024Article
- Associations of SEMA7A, SEMA4D, ADAMTS10, and ADAM8 with KRAS, NRAS, BRAF, PIK3CA, and AKT Gene Mutations, Microsatellite Instability Status, and Cytokine Expression in Colorectal Cancer Tissue.Current issues in molecular biology · 2024Article
- A disintegrin and metalloproteinase 22 activates integrin β1 through its disintegrin domain to promote the progression of pituitary adenoma.Neuro-oncology · 2024Article
- GARNL3 identified as a crucial target for overcoming temozolomide resistance in EGFRvIII-positive glioblastoma.American journal of translational research · 2024Article
- Prolonged use of temozolomide leads to increased anxiety and decreased content of aggrecan and chondroitin sulfate in brain tissues of aged rats.Biomedical reports · 2024Article
- Correlation of MR-Based Metabolomics and Molecular Profiling in the Tumor Microenvironment of Temozolomide-Treated Orthotopic GL261 Glioblastoma in Mice.International journal of molecular sciences · 2023Article
- Targeting EZH2 regulates the biological characteristics of glioma stem cells via the Notch1 pathway.Experimental brain research · 2023Article
- Intra- and Intertumoral Microglia/Macrophage Infiltration and Their Associated Molecular Signature Is Highly Variable in Canine Oligodendroglioma: A Preliminary Evaluation.Veterinary sciences · 2023Article
- Exosome-based nanoimmunotherapy targeting TAMs, a promising strategy for glioma.Cell death & disease · 2023Review
- Changes in calpain-2 expression during glioblastoma progression predisposes tumor cells to temozolomide resistance by minimizing DNA damage and p53-dependent apoptosis.Cancer cell international · 2023Article
- Identification of Dysregulated microRNAs in Glioblastoma Stem-like Cells.Brain sciences · 2023Article
- An overview of glioblastoma multiforme and temozolomide resistance: can LC-MS-based proteomics reveal the fundamental mechanism of temozolomide resistance?Frontiers in oncology · 2023Review
- Identification of co-regulated genes associated with doxorubicin resistance in the MCF-7/ADR cancer cell line.Frontiers in oncology · 2023Article
- The versatile roles of ADAM8 in cancer cell migration, mechanics, and extracellular matrix remodeling.Frontiers in cell and developmental biology · 2023Review
- Glioma stem cell signature predicts the prognosis and the response to tumor treating fields treatment.CNS neuroscience & therapeutics · 2022Article
- Proteolytically generated soluble Tweak Receptor Fn14 is a blood biomarker for γ-secretase activity.EMBO molecular medicine · 2022Article
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Authors and funding
14 authors at 4 institutions in 3 countries.
Fangyong DongDepartment of Neurosurgery, Philipps-University Marburg, Marburg, Germany (F.D., M.E., J.W.B., U.S., C.Co., S.S., B.C., C.N.); Department of Neurosurgery, Tongji Hospital, Wuhan, China (F.D.); Philipps-University Marburg, Institute for Pharmacology and Clinical Pharmacy, Marburg, Germany (A.M.D., C.Cu.); Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany (O.S., M.L.B.); BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (O.S.); Department of Neurology, Philipps-University Marburg, Marburg, Germany (H.S.); Biomaterials, Biomimetics and Biophotonics Research Group, King's College London Dental Institute, London, United Kingdom (G.K.).
Michael EibachDepartment of Neurosurgery, Philipps-University Marburg, Marburg, Germany (F.D., M.E., J.W.B., U.S., C.Co., S.S., B.C., C.N.); Department of Neurosurgery, Tongji Hospital, Wuhan, China (F.D.); Philipps-University Marburg, Institute for Pharmacology and Clinical Pharmacy, Marburg, Germany (A.M.D., C.Cu.); Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany (O.S., M.L.B.); BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (O.S.); Department of Neurology, Philipps-University Marburg, Marburg, Germany (H.S.); Biomaterials, Biomimetics and Biophotonics Research Group, King's College London Dental Institute, London, United Kingdom (G.K.).
Jörg W BartschDepartment of Neurosurgery, Philipps-University Marburg, Marburg, Germany (F.D., M.E., J.W.B., U.S., C.Co., S.S., B.C., C.N.); Department of Neurosurgery, Tongji Hospital, Wuhan, China (F.D.); Philipps-University Marburg, Institute for Pharmacology and Clinical Pharmacy, Marburg, Germany (A.M.D., C.Cu.); Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany (O.S., M.L.B.); BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (O.S.); Department of Neurology, Philipps-University Marburg, Marburg, Germany (H.S.); Biomaterials, Biomimetics and Biophotonics Research Group, King's College London Dental Institute, London, United Kingdom (G.K.).
Amalia M DolgaDepartment of Neurosurgery, Philipps-University Marburg, Marburg, Germany (F.D., M.E., J.W.B., U.S., C.Co., S.S., B.C., C.N.); Department of Neurosurgery, Tongji Hospital, Wuhan, China (F.D.); Philipps-University Marburg, Institute for Pharmacology and Clinical Pharmacy, Marburg, Germany (A.M.D., C.Cu.); Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany (O.S., M.L.B.); BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (O.S.); Department of Neurology, Philipps-University Marburg, Marburg, Germany (H.S.); Biomaterials, Biomimetics and Biophotonics Research Group, King's College London Dental Institute, London, United Kingdom (G.K.).
Uwe SchlomannDepartment of Neurosurgery, Philipps-University Marburg, Marburg, Germany (F.D., M.E., J.W.B., U.S., C.Co., S.S., B.C., C.N.); Department of Neurosurgery, Tongji Hospital, Wuhan, China (F.D.); Philipps-University Marburg, Institute for Pharmacology and Clinical Pharmacy, Marburg, Germany (A.M.D., C.Cu.); Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany (O.S., M.L.B.); BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (O.S.); Department of Neurology, Philipps-University Marburg, Marburg, Germany (H.S.); Biomaterials, Biomimetics and Biophotonics Research Group, King's College London Dental Institute, London, United Kingdom (G.K.).
Catharina ConradDepartment of Neurosurgery, Philipps-University Marburg, Marburg, Germany (F.D., M.E., J.W.B., U.S., C.Co., S.S., B.C., C.N.); Department of Neurosurgery, Tongji Hospital, Wuhan, China (F.D.); Philipps-University Marburg, Institute for Pharmacology and Clinical Pharmacy, Marburg, Germany (A.M.D., C.Cu.); Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany (O.S., M.L.B.); BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (O.S.); Department of Neurology, Philipps-University Marburg, Marburg, Germany (H.S.); Biomaterials, Biomimetics and Biophotonics Research Group, King's College London Dental Institute, London, United Kingdom (G.K.).
Susanne SchieberDepartment of Neurosurgery, Philipps-University Marburg, Marburg, Germany (F.D., M.E., J.W.B., U.S., C.Co., S.S., B.C., C.N.); Department of Neurosurgery, Tongji Hospital, Wuhan, China (F.D.); Philipps-University Marburg, Institute for Pharmacology and Clinical Pharmacy, Marburg, Germany (A.M.D., C.Cu.); Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany (O.S., M.L.B.); BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (O.S.); Department of Neurology, Philipps-University Marburg, Marburg, Germany (H.S.); Biomaterials, Biomimetics and Biophotonics Research Group, King's College London Dental Institute, London, United Kingdom (G.K.).
Oliver SchillingDepartment of Neurosurgery, Philipps-University Marburg, Marburg, Germany (F.D., M.E., J.W.B., U.S., C.Co., S.S., B.C., C.N.); Department of Neurosurgery, Tongji Hospital, Wuhan, China (F.D.); Philipps-University Marburg, Institute for Pharmacology and Clinical Pharmacy, Marburg, Germany (A.M.D., C.Cu.); Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany (O.S., M.L.B.); BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (O.S.); Department of Neurology, Philipps-University Marburg, Marburg, Germany (H.S.); Biomaterials, Biomimetics and Biophotonics Research Group, King's College London Dental Institute, London, United Kingdom (G.K.).
Martin L BiniossekDepartment of Neurosurgery, Philipps-University Marburg, Marburg, Germany (F.D., M.E., J.W.B., U.S., C.Co., S.S., B.C., C.N.); Department of Neurosurgery, Tongji Hospital, Wuhan, China (F.D.); Philipps-University Marburg, Institute for Pharmacology and Clinical Pharmacy, Marburg, Germany (A.M.D., C.Cu.); Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany (O.S., M.L.B.); BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (O.S.); Department of Neurology, Philipps-University Marburg, Marburg, Germany (H.S.); Biomaterials, Biomimetics and Biophotonics Research Group, King's College London Dental Institute, London, United Kingdom (G.K.).
Carsten CulmseeDepartment of Neurosurgery, Philipps-University Marburg, Marburg, Germany (F.D., M.E., J.W.B., U.S., C.Co., S.S., B.C., C.N.); Department of Neurosurgery, Tongji Hospital, Wuhan, China (F.D.); Philipps-University Marburg, Institute for Pharmacology and Clinical Pharmacy, Marburg, Germany (A.M.D., C.Cu.); Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany (O.S., M.L.B.); BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (O.S.); Department of Neurology, Philipps-University Marburg, Marburg, Germany (H.S.); Biomaterials, Biomimetics and Biophotonics Research Group, King's College London Dental Institute, London, United Kingdom (G.K.).
Herwig StrikDepartment of Neurosurgery, Philipps-University Marburg, Marburg, Germany (F.D., M.E., J.W.B., U.S., C.Co., S.S., B.C., C.N.); Department of Neurosurgery, Tongji Hospital, Wuhan, China (F.D.); Philipps-University Marburg, Institute for Pharmacology and Clinical Pharmacy, Marburg, Germany (A.M.D., C.Cu.); Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany (O.S., M.L.B.); BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (O.S.); Department of Neurology, Philipps-University Marburg, Marburg, Germany (H.S.); Biomaterials, Biomimetics and Biophotonics Research Group, King's College London Dental Institute, London, United Kingdom (G.K.).
Garrit KollerDepartment of Neurosurgery, Philipps-University Marburg, Marburg, Germany (F.D., M.E., J.W.B., U.S., C.Co., S.S., B.C., C.N.); Department of Neurosurgery, Tongji Hospital, Wuhan, China (F.D.); Philipps-University Marburg, Institute for Pharmacology and Clinical Pharmacy, Marburg, Germany (A.M.D., C.Cu.); Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany (O.S., M.L.B.); BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (O.S.); Department of Neurology, Philipps-University Marburg, Marburg, Germany (H.S.); Biomaterials, Biomimetics and Biophotonics Research Group, King's College London Dental Institute, London, United Kingdom (G.K.).
Barbara CarlDepartment of Neurosurgery, Philipps-University Marburg, Marburg, Germany (F.D., M.E., J.W.B., U.S., C.Co., S.S., B.C., C.N.); Department of Neurosurgery, Tongji Hospital, Wuhan, China (F.D.); Philipps-University Marburg, Institute for Pharmacology and Clinical Pharmacy, Marburg, Germany (A.M.D., C.Cu.); Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany (O.S., M.L.B.); BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (O.S.); Department of Neurology, Philipps-University Marburg, Marburg, Germany (H.S.); Biomaterials, Biomimetics and Biophotonics Research Group, King's College London Dental Institute, London, United Kingdom (G.K.).
Christopher NimskyDepartment of Neurosurgery, Philipps-University Marburg, Marburg, Germany (F.D., M.E., J.W.B., U.S., C.Co., S.S., B.C., C.N.); Department of Neurosurgery, Tongji Hospital, Wuhan, China (F.D.); Philipps-University Marburg, Institute for Pharmacology and Clinical Pharmacy, Marburg, Germany (A.M.D., C.Cu.); Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany (O.S., M.L.B.); BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (O.S.); Department of Neurology, Philipps-University Marburg, Marburg, Germany (H.S.); Biomaterials, Biomimetics and Biophotonics Research Group, King's College London Dental Institute, London, United Kingdom (G.K.).
University of Freiburg · DEKing's College London · GBTongji Hospital · CNPhilipps University of Marburg · DE
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundDespite multimodal treatment, glioblastoma (GBM) therapy with temozolomide (TMZ) remains inefficient due to chemoresistance. Matrix metalloproteinase (MMP) and a disintegrin and metalloprotease (ADAM), increased in GBM, could contribute to chemoresistance and TMZ-induced recurrence of glioblastoma.
methodsTMZ inducibility of metalloproteases was determined in GBM cell lines, primary GBM cells, and tissues from GBM and recurrent GBM. TMZ sensitivity and invasiveness of GBM cells were assessed in the presence of the metalloprotease inhibitors batimastat (BB-94) and marimastat (BB-2516). Metalloprotease-dependent effects of TMZ on mitochondria and pAkt/phosphatidylinositol-3 kinase (PI3K) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) pathways were analyzed by fluorescence activated cell sorting, morphometry, and immunoblotting. Invasiveness of GBM cells was determined by Matrigel invasion assays. Potential metalloprotease substrates were identified by proteomics and tested for invasion using blocking antibodies.
resultsTMZ induces expression of MMP-1, -9, -14, and ADAM8 in GBM cells and in recurrent GBM tissues. BB-94, but not BB-2516 (ADAM8-sparing) increased TMZ sensitivity of TMZ-resistant and -nonresistant GBM cells with different O(6)-methylguanine-DNA methyltransferase states, suggesting that ADAM8 mediates chemoresistance, which was confirmed by ADAM8 knockdown, ADAM8 overexpression, or pharmacological inhibition of ADAM8. Levels of pAkt and pERK1/2 were increased in GBM cells and correlated with ADAM8 expression, cell survival, and invasiveness. Soluble hepatocyte growth factor (HGF) R/c-met and CD44 were identified as metalloprotease substrates in TMZ-treated GBM cells. Blocking of HGF R/c-met prevented TMZ-induced invasiveness.
conclusionsADAM8 causes TMZ resistance in GBM cells by enhancing pAkt/PI3K, pERK1/2, and cleavage of CD44 and HGF R/c-met. Specific ADAM8 inhibition can optimize TMZ chemotherapy of GBM in order to prevent formation of recurrent GBM in patients.
Indexed as
ADAM ProteinsAntineoplastic AgentsBlotting, WesternBrain NeoplasmsCell SeparationCell SurvivalDacarbazineDrug Resistance, NeoplasmEnzyme-Linked Immunosorbent AssayFluorescence Resonance Energy TransferGlioblastomaHumansImmunoblottingMembrane ProteinsNeoplasm InvasivenessReal-Time Polymerase Chain ReactionADAM8 protein, humanADAM ProteinsAntineoplastic AgentsDacarbazineMembrane ProteinsTemozolomidechemoresistanceglioblastomahydroxamate inhibitorsmetalloproteasesTMZ
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