The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego 9500 Gilman Drive, La Jolla, CA, 92093-0815, USA.
Division of Medical Genetics, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
Sci Rep. 2020 May 20;10(1):8348. doi: 10.1038/s41598-020-65320-6.
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 Ca 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.
迄今为止，胶质母细胞瘤（GBM）的现有治疗方法大多无效。未解决的未折叠蛋白反应（UPR）诱导细胞凋亡代表了一种新的潜在治疗策略。在这里，我们测试了 12ADT（肌浆内质网 Ca2+-ATP 酶（SERCA）抑制剂）对一组未经选择的患者来源的神经球形成细胞的影响，发现 GBM 细胞可以分为“应答者”和“非应答者”。通过 RNAseq 分析，我们发现非应答表型与 UPR 基因的表达显著相关，特别是 ERN1（IRE1）和 ATF4。我们还鉴定了另外两个在非应答者中选择性过表达的基因，IGFBP3 和 IGFBP5。在 U251 人 GBM 细胞系中，CRISPR 介导的 ERN1、IGFBP3、IGFBP5 特征基因缺失增加了对 12ADT 的反应性。值得注意的是，在癌症基因组图谱中的>65%的 GBM 病例表达非应答者（ERN1、IGFBP3、IGFBP5）基因特征。因此，IRE1α 和 IGFBPs 的高水平预示着对诱导未解决 UPR 的药物以及可能的其他形式的化疗反应不良，有助于更好地对 GBM 患者进行分层。
