The metalloprotease-disintegrin ADAM8 contributes to temozolomide chemoresistance and enhanced invasiveness of human glioblastoma cells

Dong, Feihong; Eibach, Michael; Bartsch, Jörg W.; Dolga, Amalia M.; Schlomann, Uwe; Conrad, Catharina; Schieber, Susanne; Schilling, Oliver; Biniossek, Martin L.; Culmsee, Carsten; Strik, Herwig; Koller, Garrit; Carl, Barbara; Nimsky, Christopher

doi:10.1093/neuonc/nov042

Cited by 56 publications

(51 citation statements)

References 47 publications

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“…Synthetic fluorescence‐labelled peptides were used to monitor protease activities of ADAM8 in cell supernatants as previously described . Fluorescence was detected at emission 460 nm with excitation 355 nm on Turner Quantech IR Fluorometer (Cole‐Parmer, Vernon Hills, IL, USA).…”

Section: Methodsmentioning

confidence: 99%

Propofol inhibits pancreatic cancer progress under hypoxia via ADAM8

Gao

Zhang

et al. 2019

J Hepato Biliary Pancreat

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Background To investigate the potential anti-tumoral properties of propofol in pancreatic cancer and elucidate the underlying mechanisms. Methods The relative expression of ADAM metallopeptidase domain 8 (ADAM8) in response to hypoxia in Panc1 cells was analyzed by western blotting. The enzymatic activity was determined by fluorescence release from PEPDAB013 decomposition. Cell growth was measured via cell counting and cell viability was measured using CCK-8 kit. Cell migrative capacity was evaluated by transwell and adhesion assay. The relative abundance of angiogenesis-related markers including platelet-derived growth factor AA, angiogenin, endothelin-1 and vascular endothelial growth factor were determined by real-time polymerase chain reaction and western blotting. The antitumoral activity of propofol was investigated with Panc1derived xenograft mice model. Results ADAM8 was significantly induced by hypoxia and efficiently inhibited by co-treatment with propofol. Propofol suppressed proliferation and compromised viability of Panc1 cells. In addition, the migrative capacity was greatly inhibited by propofol dosage. Comprehensive profiling of angiogenesis-related markers demonstrated that propofol remarkably suppressed neovascularization response in Panc1 cells under hypoxia. We further uncovered that propofol administration via subcutaneous injection delayed xenograft tumor progression. Conclusion Propofol specifically inhibited ADAM8 expression and activation in response to hypoxia in pancreatic cancer, and held great value for therapeutic effects.

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Section: Methodsmentioning

confidence: 99%

Propofol inhibits pancreatic cancer progress under hypoxia via ADAM8

Gao

Zhang

et al. 2019

J Hepato Biliary Pancreat

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“…Using Kiloplex ELISA‐based array, we detected 38 proteins significantly accumulated in the supernatant of TMZ‐treated glioma cells and in the supernatant of MMP14‐overexpressing U87 glioma cells (Supplemental Tables S1 and S2) including MMP2, Plexin B3, Activin A, Draxin and DLL4. Among highly expressed proteins, the DLL4 was of most interest since it was the only one to be associated with negative prognosis un GBM patients: TMZ has no effect on secretion of MMP2 in A172 and U373 cells and recurrent GBM, Plexin B3 plays anti‐glioma role, inhibiting cell motility and does not correlate with GBM patient survival, similar to Activin A (using TCGA and Rembrandt databases) and Draxin (Kamoun, Murat, Ducray and Gravendeel databases, data not shown) expressions.…”

Section: Resultsmentioning

confidence: 98%

“…Using Kiloplex ELISA-based array, we detected 38 proteins significantly accumulated in the supernatant of TMZ-treated glioma cells and in the supernatant of MMP14-overexpressing U87 glioma cells (Supplemental Tables S1 and S2) including MMP2, Plexin B3, Activin A, Draxin and DLL4. Among highly expressed proteins, the DLL4 was of most interest since it was the only one to be associated with negative prognosis un GBM patients 41 : TMZ has no effect on secretion of MMP2 in A172 and U373 cells 42 and recurrent GBM, 43 Plexin B3 plays anti-glioma role, 44 inhibiting cell motility and does not correlate with GBM patient survival, 45 similar to Activin A (using TCGA and Rembrandt databases) and DLL4 is a known ligand of Notch receptor Types 1 and 3, which stimulates release of Notch intracellular domain (NICD) by γ-secretase, followed by NICD nuclear translocation, 46 activation of transcription of genes such as HES 47 and promotion of stemness. 33,34 Treatment of U87 and GBM43 glioma cells with recombinant human DLL4 demonstrates white colocalization of signals from activated Notch3 (NICD3) and expression of MMP14 (Fig.…”

Section: Tmz-induced Mmp14 Promotes Glioma Stemness Via Dll4-notch3 Axismentioning

confidence: 99%

TMZ regulates GBM stemness via MMP14‐DLL4‐Notch3 pathway

Ulasov

Mijanović

Savchuk

et al. 2019

Intl Journal of Cancer

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Glioblastoma (GBM) is one of the most aggressive primary brain tumors with frequent recurrences following the standard methods of treatment—temozolomide (TMZ), ionizing radiation and surgical resection. The objective of our study was to investigate GBM resistance mediated via MMP14 (matrix metalloproteinase 14). We used multiple PDX GBM models and established glioma cell lines to characterize expression and subcellular localization of MMP14 after TMZ treatment. We performed a Kiloplex ELISA‐based array to evaluate changes in cellular proteins induced by MMP14 expression and translocation. Lastly, we conducted functional and mechanistic studies to elucidate the role of DLL4 (delta‐like canonical notch ligand 4) in regulation of glioma stemness, particularly in the context of its relationship to MMP14. We detected that TMZ treatment promotes nuclear translocation of MMP14 followed by extracellular release of DLL4. DLL4 in turn stimulates cleavage of Notch3, its nuclear translocation and induction of sphering capacity and stemness.

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“…Primary cell lines (N5, N9, and N33) were derived from GBM patients who underwent surgery at Tiantan Hospital according to a protocol reported by Dong et al [24] EGFRvIII cell lines were generated via infection of the cells with lentiviruses expressing EGFRvIII (GV341-EGFRvIII) followed by puromycin selection. Primary cell lines (N5, N9, and N33) were derived from GBM patients who underwent surgery at Tiantan Hospital according to a protocol reported by Dong et al [24] EGFRvIII cell lines were generated via infection of the cells with lentiviruses expressing EGFRvIII (GV341-EGFRvIII) followed by puromycin selection.…”

Section: Methodsmentioning

confidence: 99%

Genome‐Wide CRISPR‐Cas9 Screening Identifies NF‐κB/E2F6 Responsible for EGFRvIII‐Associated Temozolomide Resistance in Glioblastoma

Huang

Liu

et al. 2019

Advanced Science

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Amplification of epidermal growth factor receptor (EGFR) and active mutant EGFRvIII occurs frequently in glioblastoma (GBM) and contributes to chemo/radio‐resistance in various cancers, especially in GBM. Elucidating the underlying molecular mechanism of temozolomide (TMZ) resistance in GBM could benefit cancer patients. A genome‐wide screening under a clustered regularly interspaced short palindromic repeats (CRISPR)‐Cas9 library is conducted to identify the genes that confer resistance to TMZ in EGFRvIII‐expressing GBM cells. Deep sgRNA sequencing reveals 191 candidate genes that are responsible for TMZ resistance in EGFRvIII‐expressing GBM cells. Notably, E2F6 is proven to drive a TMZ resistance, and E2F6 expression is controlled by the EGFRvIII/AKT/NF‐κB pathway. Furthermore, E2F6 is shown as a promising therapeutic target for TMZ resistance in orthotopic GBM cell line xenografts and GBM patient‐derived xenografts models. After integrating clinical data with paired primary–recurrent RNA sequencing data from 134 GBM patients who received TMZ treatment after surgery, it has been revealed that the E2F6 expression level is a predictive marker for TMZ response. Therefore, the inhibition of E2F6 is a promising strategy to conquer TMZ resistance in GBM.

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The metalloprotease-disintegrin ADAM8 contributes to temozolomide chemoresistance and enhanced invasiveness of human glioblastoma cells

Abstract: ADAM8 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.

Cited by 56 publications

References 47 publications

Propofol inhibits pancreatic cancer progress under hypoxia via ADAM8

Propofol inhibits pancreatic cancer progress under hypoxia via ADAM8

TMZ regulates GBM stemness via MMP14‐DLL4‐Notch3 pathway

Genome‐Wide CRISPR‐Cas9 Screening Identifies NF‐κB/E2F6 Responsible for EGFRvIII‐Associated Temozolomide Resistance in Glioblastoma

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