15417786mcr170120-sup-180095_2_supp_4066975_hqphph.pdf (574.36 kB)
Supplementary figures 1 to 6 from Phostine PST3.1a Targets MGAT5 and Inhibits Glioblastoma-Initiating Cell Invasiveness and Proliferation
journal contribution
posted on 2023-04-03, 16:29 authored by Zahra Hassani, Ali Saleh, Soumaya Turpault, Salim Khiati, Willy Morelle, Jacques Vignon, Jean-Philippe Hugnot, Emmanuelle Uro-Coste, Philippe Legrand, Marcel Delaforge, Séverine Loiseau, Ludovic Clarion, Marc Lecouvey, Jean-Noël Volle, David Virieux, Jean-Luc Pirat, Hugues Duffau, Norbert BakalaraSupplementary figures providing additionnal information concerning: - The cells glycome before and after PST3.1a treatment as measured by mass spectrometry (Supp. Figure 1) or Glycoprofile (Supp. Figure 2) - The absence of effect of PST3.1a on O-Glycosylation (Supp. Figure 3) - Western blot quantifications (Supp. Figure 4) - The inhibition of cell invasion in matrigel by PST3.1a (Supp. Figure 5) - The absence of cytotoxicity on non-proliferating PBMC cells (Supp. Figure 6).
Funding
ANR-PCV (G2O)
ANR Emergence-Bio
INCA (formation des medecins)
European Community
History
ARTICLE ABSTRACT
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.Usage metrics
Keywords
Cell CycleSignal transduction pathwaysCell SignalingCns CancersDrug MechanismsCellular responses to anticancer drugsGenome BiologySilencing and reactivation of gene expressionProgression, Invasion & MetastasisCell adhesion and extracellular matrixMigration and invasionProteomicsSmall Molecule Agents
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC