IRE1α and IGF signaling predict resistance to an endoplasmic reticulum stress-inducing drug in glioblastoma cells
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...
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doaj-f7db2ed01eae4e36a861f57c2de403b22021-05-23T11:37:13ZengNature Publishing GroupScientific Reports2045-23222020-05-0110111210.1038/s41598-020-65320-6IRE1α and IGF signaling predict resistance to an endoplasmic reticulum stress-inducing drug in glioblastoma cellsJeffrey J. Rodvold0Su Xian1Julia Nussbacher2Brian Tsui3T. Cameron Waller4Stephen C. Searles5Alyssa Lew6Pengfei Jiang7Ivan Babic8Natsuko Nomura9Jonathan H. Lin10Santosh Kesari11Hannah Carter12Maurizio Zanetti13The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego 9500 Gilman DriveDivision of Medical Genetics, Department of Medicine, University of California, San Diego, 9500 Gilman DriveDepartment of Cellular and Molecular Medicine, University of California, San DiegoDivision of Medical Genetics, Department of Medicine, University of California, San Diego, 9500 Gilman DriveDivision of Medical Genetics, Department of Medicine, University of California, San Diego, 9500 Gilman DriveThe Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego 9500 Gilman DriveThe Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego 9500 Gilman DriveDepartment of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute/Pacific Neuroscience Institute, 2200 Santa Monica BoulevardDepartment of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute/Pacific Neuroscience Institute, 2200 Santa Monica BoulevardDepartment of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute/Pacific Neuroscience Institute, 2200 Santa Monica BoulevardDepartment of Pathology, Stanford UniversityDepartment of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute/Pacific Neuroscience Institute, 2200 Santa Monica BoulevardDivision of Medical Genetics, Department of Medicine, University of California, San Diego, 9500 Gilman DriveThe Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego 9500 Gilman DriveAbstract 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.https://doi.org/10.1038/s41598-020-65320-6 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jeffrey J. Rodvold Su Xian Julia Nussbacher Brian Tsui T. Cameron Waller Stephen C. Searles Alyssa Lew Pengfei Jiang Ivan Babic Natsuko Nomura Jonathan H. Lin Santosh Kesari Hannah Carter Maurizio Zanetti |
spellingShingle |
Jeffrey J. Rodvold Su Xian Julia Nussbacher Brian Tsui T. Cameron Waller Stephen C. Searles Alyssa Lew Pengfei Jiang Ivan Babic Natsuko Nomura Jonathan H. Lin Santosh Kesari Hannah Carter Maurizio Zanetti IRE1α and IGF signaling predict resistance to an endoplasmic reticulum stress-inducing drug in glioblastoma cells Scientific Reports |
author_facet |
Jeffrey J. Rodvold Su Xian Julia Nussbacher Brian Tsui T. Cameron Waller Stephen C. Searles Alyssa Lew Pengfei Jiang Ivan Babic Natsuko Nomura Jonathan H. Lin Santosh Kesari Hannah Carter Maurizio Zanetti |
author_sort |
Jeffrey J. Rodvold |
title |
IRE1α and IGF signaling predict resistance to an endoplasmic reticulum stress-inducing drug in glioblastoma cells |
title_short |
IRE1α and IGF signaling predict resistance to an endoplasmic reticulum stress-inducing drug in glioblastoma cells |
title_full |
IRE1α and IGF signaling predict resistance to an endoplasmic reticulum stress-inducing drug in glioblastoma cells |
title_fullStr |
IRE1α and IGF signaling predict resistance to an endoplasmic reticulum stress-inducing drug in glioblastoma cells |
title_full_unstemmed |
IRE1α and IGF signaling predict resistance to an endoplasmic reticulum stress-inducing drug in glioblastoma cells |
title_sort |
ire1α and igf signaling predict resistance to an endoplasmic reticulum stress-inducing drug in glioblastoma cells |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2020-05-01 |
description |
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. |
url |
https://doi.org/10.1038/s41598-020-65320-6 |
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