IRE1α and IGF signaling predict resistance to an endoplasmic reticulum stress-inducing drug in glioblastoma cells.
Jeffrey J RodvoldSu XianJulia NussbacherBrian Y TsuiT Cameron WallerStephen C SearlesAlyssa LewPengfei JiangIvan BabicNatsuko NomuraJonathan H LinSantosh KesariHannah CarterMaurizio ZanettiPublished in: Scientific reports (2020)
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.
Keyphrases
- endoplasmic reticulum stress
- induced apoptosis
- genome wide
- cell cycle arrest
- end stage renal disease
- oxidative stress
- ejection fraction
- poor prognosis
- signaling pathway
- cell death
- chronic kidney disease
- crispr cas
- binding protein
- gene expression
- transcription factor
- squamous cell carcinoma
- peritoneal dialysis
- bioinformatics analysis
- genome editing
- papillary thyroid
- protein kinase
- amino acid
- rectal cancer
- patient reported
- chemotherapy induced
- lymph node metastasis
- endoplasmic reticulum