Molecular cancer research, 2017-10, Vol.15 (10), p.1376-1387
2017
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- Autor(en) / Beteiligte
- Titel
- Phostine PST3.1a Targets MGAT5 and Inhibits Glioblastoma-Initiating Cell Invasiveness and Proliferation
- Ist Teil von
- Molecular cancer research, 2017-10, Vol.15 (10), p.1376-1387
- Ort / Verlag
- United States: American Association for Cancer Research Inc
- Erscheinungsjahr
- 2017
- Quelle
- EZB-FREE-00999 freely available EZB journals
- Beschreibungen/Notizen
- Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and accounts for a significant proportion of all primary brain tumors. Median survival after treatment is around 15 months. Remodeling of N-glycans by the N-acetylglucosamine glycosyltransferase (MGAT5) regulates tumoral development. Here, perturbation of MGAT5 enzymatic activity by the small-molecule inhibitor 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl2-oxo-2λ5-[1,2]oxaphosphinane (PST3.1a) restrains GBM growth. In cell-based assays, it is demonstrated that PST3.1a alters the β1,6-GlcNAc N-glycans of GBM-initiating cells (GIC) by inhibiting MGAT5 enzymatic activity, resulting in the inhibition of TGFβR and FAK signaling associated with doublecortin (DCX) upregulation and increase oligodendrocyte lineage transcription factor 2 (OLIG2) expression. PST3.1a thus affects microtubule and microfilament integrity of GBM stem cells, leading to the inhibition of GIC proliferation, migration, invasiveness, and clonogenic capacities. Orthotopic graft models of GIC revealed that PST3.1a treatment leads to a drastic reduction of invasive and proliferative capacity and to an increase in overall survival relative to standard temozolomide therapy. Finally, bioinformatics analyses exposed that PST3.1a cytotoxic activity is positively correlated with the expression of genes of the epithelial-mesenchymal transition (EMT), while the expression of mitochondrial genes correlated negatively with cell sensitivity to the compound. These data demonstrate the relevance of targeting MGAT5, with a novel anti-invasive chemotherapy, to limit glioblastoma stem cell invasion. .
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1541-7786eISSN: 1557-3125DOI: 10.1158/1541-7786.mcr-17-0120Titel-ID: cdi_hal_primary_oai_HAL_hal_01610960v1
- Format
- –
- Schlagworte
- Animals, Bioinformatics, Brain, Brain cancer, Brain Neoplasms - drug therapy, Brain Neoplasms - metabolism, Brain tumors, Cancer, Cell Line, Tumor, Cell Movement, Cell proliferation, Cell Proliferation - drug effects, Chemical Sciences, Chemotherapy, Cyclic P-Oxides - administration & dosage, Cyclic P-Oxides - pharmacology, Cytotoxicity, Doublecortin protein, Enzymatic activity, Epithelial-Mesenchymal Transition - drug effects, Gene expression, Gene Expression Regulation, Neoplastic - drug effects, Genes, Glioblastoma, Glioblastoma - drug therapy, Glioblastoma - metabolism, Glycosyltransferase, Humans, Inhibition, Invasiveness, Mesenchyme, Mice, Mitochondria, N-Acetylglucosamine, N-Acetylglucosaminyltransferases - metabolism, N-glycans, Neoplasm Invasiveness, Neoplastic Stem Cells - drug effects, Olig2 protein, Organic chemistry, Polysaccharides, Signal Transduction - drug effects, Signaling, Small Molecule Libraries - administration & dosage, Small Molecule Libraries - pharmacology, Stem cells, Survival, Temozolomide, Xenograft Model Antitumor Assays