1. IRE1α and IGF signaling predict resistance to an endoplasmic reticulum stress-inducing drug in glioblastoma cells.
- Author
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Rodvold, Jeffrey J, Xian, Su, Nussbacher, Julia, Tsui, Brian, Cameron Waller, T, Searles, Stephen C, Lew, Alyssa, Jiang, Pengfei, Babic, Ivan, Nomura, Natsuko, Lin, Jonathan H, Kesari, Santosh, Carter, Hannah, and Zanetti, Maurizio
- Subjects
Brain ,Cell Line ,Tumor ,Spheroids ,Cellular ,Tumor Cells ,Cultured ,Humans ,Glioblastoma ,Brain Neoplasms ,Thapsigargin ,Endoribonucleases ,Protein-Serine-Threonine Kinases ,Insulin-Like Growth Factor Binding Protein 3 ,Insulin-Like Growth Factor Binding Protein 5 ,Signal Transduction ,Apoptosis ,Gene Expression Regulation ,Neoplastic ,Drug Resistance ,Neoplasm ,Adult ,Sarcoplasmic Reticulum Calcium-Transporting ATPases ,Unfolded Protein Response ,Primary Cell Culture ,Endoplasmic Reticulum Stress ,Progression-Free Survival ,RNA-Seq ,Neurosciences ,Rare Diseases ,Genetics ,Cancer ,Brain Disorders ,Brain Cancer ,2.1 Biological and endogenous factors - 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.
- Published
- 2020