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

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-25-[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 wit...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Oncogenes and Tumor Suppressors Source Type: research

Related Links:

This article is protected by copyright. All rights reserved. PMID: 31922313 [PubMed - as supplied by publisher]
Source: Anatomical Record - Category: Anatomy Authors: Tags: Anat Rec (Hoboken) Source Type: research
lin Wickström Medulloblastoma is one of the most common malignant brain tumor types in children, with an overall survival of 70%. Mortality is associated with metastatic relapsed tumors. Rho-associated kinases (ROCKs), important for epithelial-mesenchymal transition (EMT) and proper nervous system development, have previously been identified as a promising drug target to inhibit cancer growth and metastatic spread. Here, we show that ROCKs are expressed in medulloblastoma, with higher ROCK2 mRNA expression in metastatic compared to non-metastatic tumors. By evaluating three ROCK inhibitors in a panel of medullobla...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
CONCLUSIONS: MiR-491 overexpression inhibited the proliferation through the Wnt3a/β-catenin pathway and invasion-mediated EMT in glioma. The newly identified miR-491/Wnt3a/β-catenin axis provides novel insight into the pathogenesis of glioma. PMID: 31858558 [PubMed - in process]
Source: European Review for Medical and Pharmacological Sciences - Category: Drugs & Pharmacology Tags: Eur Rev Med Pharmacol Sci Source Type: research
Publication date: Available online 22 October 2019Source: Seminars in Cancer BiologyAuthor(s): Tamara T. Lah, Metka Novak, Barbara BreznikAbstractBrain, the major organ of the central nervous system controls and processes most of body activities. Therefore, the most aggressive brain tumor – glioblastoma and metastases from other organs to the brain are lethal leaving the patients with very short time of survival. The brain tissue landscape is very different from any other tissues and the specific microenvironment, comprising stem cells niches and blood-brain barrier, significantly influences the low rate of glioblast...
Source: Seminars in Cancer Biology - Category: Cancer & Oncology Source Type: research
Authors: Zou S, Zhang D, Xu Z, Wen X, Zhang Y Abstract Histone H3K27 demethylase Jumonji domain-containing protein 3 (JMJD3) is involved in somatic cell differentiation and tumor progression; however, the underlying mechanisms of JMJD3 in cancer progression are yet to be fully explored. To improve understanding regarding the function of JMJD3 in brain tumor cells, the present study investigated the effects of JMJD3 on the epithelial-mesenchymal transition (EMT) and migration in glioma cells, and the underlying mechanisms involving the C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C motif chemokine receptor 4 (CXCR4)...
Source: Oncology Letters - Category: Cancer & Oncology Tags: Oncol Lett Source Type: research
Conclusion: As a prognostic factor, Orai2 is obviously activated in the classical and mesenchymal subtypes of GBM and promotes glioma cell self-renewal, apoptosis, and EMT-like by the JNK pathway. These findings indicate that Orai2 could be a candidate prognostic and therapeutic target, especially for the classical and mesenchymal subtypes of GBM. PMID: 31772693 [PubMed - in process]
Source: Disease Markers - Category: Laboratory Medicine Tags: Dis Markers Source Type: research
amuel Weiss In glioblastoma (GBM), brain tumor stem cells (BTSCs) encompass heterogenous populations of multipotent, self-renewing, and tumorigenic cells, which have been proposed to be at the root of therapeutic resistance and recurrence. While the functional significance of BTSC heterogeneity remains to be fully determined, we previously distinguished relatively quiescent stem-like precursor state from the more aggressive progenitor-like precursor state. In the present study, we hypothesized that progenitor-like BTSCs arise from stem-like precursors through a mesenchymal transition and drive post-treatment recurrence...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
AbstractGliomas are the most commonly occurring tumors of the central nervous system. Glioblastoma multiforme (GBM) is the most malignant and aggressive brain cancer in adults. Further understanding of the mechanisms underlying the aggressive nature of GBM is urgently needed. Here we identified homeobox B8 (HOXB8), a member of the homeobox family, as a crucial contributor to the aggressiveness of GBM. Data mining of publicly accessible RNA sequence datasets and our patient cohorts confirmed a higher expression of HOXB8 in the tumor tissue of GBM patients, and a strong positive correlation between the expression level and p...
Source: Neuroscience Bulletin - Category: Neuroscience Source Type: research
In conclusion, 27-HC, a primary metabolite of cholesterol, may serve an important role in the progression of glioblastoma. PMID: 31579088 [PubMed]
Source: Oncology Letters - Category: Cancer & Oncology Tags: Oncol Lett Source Type: research
Park Chung Kang Despite the presence of aggressive treatment strategies, glioblastoma remains intractable, warranting a novel therapeutic modality. An oral antipsychotic agent, penflurido (PFD), used for schizophrenia treatment, has shown an antitumor effect on various types of cancer cells. As glioma sphere-forming cells (GSCs) are known to mediate drug resistance in glioblastoma, and considering that antipsychotics can easily penetrate the blood-brain barrier, we investigated the antitumor effect of PFD on patient-derived GSCs. Using five GSCs, we found that PFD exerts an antiproliferative effect in a time- an...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
More News: Brain | Brain Cancers | Brain Tumor | Cancer | Cancer & Oncology | Chemotherapy | Epithelial Cancer | Genetics | Neurology | Stem Cell Therapy | Stem Cells | Temodar