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Differential Response of Glioma Stem Cells to Arsenic Trioxide Therapy Is Regulated by MNK1 and mRNA Translation.
- Source :
-
Molecular cancer research : MCR [Mol Cancer Res] 2018 Jan; Vol. 16 (1), pp. 32-46. Date of Electronic Publication: 2017 Oct 17. - Publication Year :
- 2018
-
Abstract
- Mesenchymal (MES) and proneural (PN) are two distinct glioma stem cell (GSC) populations that drive therapeutic resistance in glioblastoma (GBM). We screened a panel of 650 small molecules against patient-derived GBM cells to discover compounds targeting specific GBM subtypes. Arsenic trioxide (ATO), an FDA-approved drug that crosses the blood-brain barrier, was identified as a potent PN-specific compound in the initial screen and follow-up validation studies. Furthermore, MES and PN GSCs exhibited differential sensitivity to ATO. As ATO has been shown to activate the MAPK-interacting kinase 1 (MNK1)-eukaryotic translation initiation factor 4E (eIF4E) pathway and subsequent mRNA translation in a negative regulatory feedback manner, the mechanistic role of ATO resistance in MES GBM was explored. In GBM cells, ATO-activated translation initiation cellular events via the MNK1-eIF4E signaling axis. Furthermore, resistance to ATO in intracranial PDX tumors correlated with high eIF4E phosphorylation. Polysomal fractionation and microarray analysis of GBM cells were performed to identify ATO's effect on mRNA translation and enrichment of anti-apoptotic mRNAs in the ATO-induced translatome was found. Additionally, it was determined that MNK inhibition sensitized MES GSCs to ATO in neurosphere and apoptosis assays. Finally, examination of the effect of ATO on patients from a phase I/II clinical trial of ATO revealed that PN GBM patients responded better to ATO than other subtypes as demonstrated by longer overall and progression-free survival. Implications: These findings raise the possibility of a unique therapeutic approach for GBM, involving MNK1 targeting to sensitize MES GSCs to drugs like arsenic trioxide. Mol Cancer Res; 16(1); 32-46. ©2017 AACR .<br /> (©2017 American Association for Cancer Research.)
- Subjects :
- Animals
Cell Line, Tumor
Cell Proliferation drug effects
Glioma pathology
Humans
Intracellular Signaling Peptides and Proteins metabolism
Mice
Neoplastic Stem Cells metabolism
Neoplastic Stem Cells pathology
Protein Serine-Threonine Kinases metabolism
RNA, Messenger metabolism
Signal Transduction
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Arsenic Trioxide pharmacology
Glioma drug therapy
Intracellular Signaling Peptides and Proteins genetics
Protein Serine-Threonine Kinases genetics
RNA, Messenger genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3125
- Volume :
- 16
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular cancer research : MCR
- Publication Type :
- Academic Journal
- Accession number :
- 29042487
- Full Text :
- https://doi.org/10.1158/1541-7786.MCR-17-0397