Abstract
To date current therapies of glioblastoma multiforme (GBM) are largely ineffective. The induction of apoptosis by an unresolvable unfolded protein response (UPR) represents a potential new therapeutic strategy. Here we tested 12ADT, a sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) inhibitor, on a panel of unselected patient-derived neurosphere-forming cells and found that GBM cells can be distinguished into "responder" and "non-responder". By RNASeq analysis we found that the non-responder phenotype is significantly linked with the expression of UPR genes, and in particular ERN1 (IRE1) and ATF4. We also identified two additional genes selectively overexpressed among non-responders, IGFBP3 and IGFBP5. CRISPR-mediated deletion of the ERN1, IGFBP3, IGFBP5 signature genes in the U251 human GBM cell line increased responsiveness to 12ADT. Remarkably, >65% of GBM cases in The Cancer Genome Atlas express the non-responder (ERN1, IGFBP3, IGFBP5) gene signature. Thus, elevated levels of IRE1α and IGFBPs predict a poor response to drugs inducing unresolvable UPR and possibly other forms of chemotherapy helping in a better stratification GBM patients.
Publication types
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Observational Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Apoptosis / drug effects
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Brain / pathology
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Brain / surgery
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / genetics
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Brain Neoplasms / mortality
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Brain Neoplasms / surgery
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Cell Line, Tumor
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Drug Resistance, Neoplasm / genetics
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Endoplasmic Reticulum Stress / drug effects
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Endoribonucleases / genetics
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Endoribonucleases / metabolism*
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Gene Expression Regulation, Neoplastic
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Glioblastoma / drug therapy*
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Glioblastoma / genetics
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Glioblastoma / mortality
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Glioblastoma / surgery
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Humans
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Insulin-Like Growth Factor Binding Protein 3 / genetics
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Insulin-Like Growth Factor Binding Protein 3 / metabolism
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Insulin-Like Growth Factor Binding Protein 5 / genetics
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Insulin-Like Growth Factor Binding Protein 5 / metabolism
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Primary Cell Culture
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Progression-Free Survival
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA-Seq
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Sarcoplasmic Reticulum Calcium-Transporting ATPases / antagonists & inhibitors*
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Signal Transduction / genetics
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Spheroids, Cellular
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Thapsigargin / analogs & derivatives
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Thapsigargin / pharmacology*
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Thapsigargin / therapeutic use
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Tumor Cells, Cultured
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Unfolded Protein Response / drug effects
Substances
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IGFBP3 protein, human
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IGFBP5 protein, human
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Insulin-Like Growth Factor Binding Protein 3
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Insulin-Like Growth Factor Binding Protein 5
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Thapsigargin
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ERN1 protein, human
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Protein Serine-Threonine Kinases
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Endoribonucleases
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Sarcoplasmic Reticulum Calcium-Transporting ATPases