Cbmt-14. Exploiting Vulnerabilities of the Mesenchymal Subtype of Glioma Stem-like Cells to Endoplasmic Reticulum Stress
Year: 2018
Type: conference-abstract
Abstract: Transcriptome profiling of glioma stem-like cells (GSCs) show differences in biological properties depending on their expression signature. Mesenchymal (MES) GSCs are generally associated with increased treatment resistance, thus it is important to identify essential molecules that promote their survival. Here, we discover the preferentially higher expression of the endoplasmic reticulum (ER) chaperone protein glucose-regulated protein 78 (GRP78) in the MES subtype of glioblastomas (GBMs) and derivative GSCs. MES GSCs showed lesser activated basal unfolded protein response (UPR) compared to its proneural (PN) counterparts. GRP78 knockdown in GSCs increased the basal level of UPR and enhanced tunicamycin induced apoptosis. GSCs expressing high levels of GRP78 concomitantly possess higher content of protein and lipid droplets (LDs). As shown by metabolomics studies we have performed in MES GSCs, silencing GRP78 stimulated biosynthesis of lipids that we hypothesize might protect MES GSCs from ER stress induced reactivation oxygen species (ROS) accumulation and apoptosis. In fact, concomitant treatment with simvastatin, a cholesterol inhibitor, induced apoptosis in cells with silenced GRP78 in vitro and significantly improved survival in vivo. Our study shows that higher GRP78 expression and lipid biosynthesis in MES GSC might act as protective mechanisms from ER and oxidative stress, which can be exploited for therapeutic targeting of the MES subtype of GSCs.
Source: Neuro-Oncology
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2899680133