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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Nature Portfolio
2020
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oai:doaj.org-article:f7db2ed01eae4e36a861f57c2de403b22021-12-02T14:59:09ZIRE1α and IGF signaling predict resistance to an endoplasmic reticulum stress-inducing drug in glioblastoma cells10.1038/s41598-020-65320-62045-2322https://doaj.org/article/f7db2ed01eae4e36a861f57c2de403b22020-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-65320-6https://doaj.org/toc/2045-2322Abstract 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.Jeffrey J. RodvoldSu XianJulia NussbacherBrian TsuiT. Cameron WallerStephen C. SearlesAlyssa LewPengfei JiangIvan BabicNatsuko NomuraJonathan H. LinSantosh KesariHannah CarterMaurizio ZanettiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020) |
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Medicine R Science Q |
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Medicine R Science Q 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 |
| 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. |
| format |
article |
| 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 |
| 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 Portfolio |
| publishDate |
2020 |
| url |
https://doaj.org/article/f7db2ed01eae4e36a861f57c2de403b2 |
| work_keys_str_mv |
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1718389239579672576 |