Titre :

Phostine PST3.1a Targets MGAT5 and Inhibits Glioblastoma-Initiating Cell Invasiveness and Proliferation

Auteur(s) :

Hassani, Zahra [Auteur]
Saleh, Ali [Auteur]
Turpault, Soumaya [Auteur]
Khiati, Salim [Auteur]
Morelle, Willy [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Vignon, Jacques [Auteur]
Hugnot, Jean-Philippe [Auteur]
Uro-Coste, Emmanuelle [Auteur]
Legrand, Philippe [Auteur]
Delaforge, Marcel [Auteur]
Loiseau, Séverine [Auteur]
Clarion, Ludovic [Auteur]
Lecouvey, Marc [Auteur]
Volle, Jean-Noël [Auteur]
Virieux, David [Auteur]
Pirat, Jean-Luc [Auteur]
Duffau, Hugues [Auteur]
Bakalara, Norbert [Auteur]

Titre de la revue :

Molecular cancer research. MCR

Nom court de la revue :

Mol. Cancer Res.

Numéro :

15

Pagination :

1376-1387

Date de publication :

2017-10

ISSN :

1557-3125

Mot(s)-clé(s) en anglais :

Cell Proliferation
Signal Transduction
Neoplasm Invasiveness
Humans
Gene Expression Regulation, Neoplastic
Cyclic P-Oxides
Glioblastoma
Neoplastic Stem Cells
N-Acetylglucosaminyltransferases
Brain Neoplasms
Xenograft Model Antitumor Assays
Animals
Small Molecule Libraries
Epithelial-Mesenchymal Transition
Cell Line, Tumor
Mice
Cell Movement

Discipline(s) HAL :

Chimie/Chimie théorique et/ou physique

Résumé en anglais : [en]

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 ...
Lire la suite >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. Mol Cancer Res; 15(10); 1376-87. ©2017 AACR.Lire moins >

Langue :

Anglais

Établissement(s) :

CNRS
Université de Lille

Collections :

• Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Équipe(s) de recherche :

Mécanismes moléculaires de la N-glycosylation et pathologies associées

Date de dépôt :

2020-02-12T15:11:58Z