Targeting Glioblastoma Stem Cells with 2-Deoxy-D-Glucose (2-DG) Potentiates Radiation-Induced Unfolded Protein Response (UPR)

Cancers

Alexis Musick¹  JeffreyS. Prince¹  Steven Vanni²  Eric Barbarite³  ReginaM. Graham³  Nicolas de Cordoba³  WinstonM. Walters³  RicardoJ. Komotar³  MeganM. Marlow³  GregorA. Rodriguez³  SumedhS. Shah³  Brian Marples³ 

[1] Dauer Electron Microscopy Laboratory, Department of Biology, University of Miami, Coral Gables, FL 33146, USA;Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA;University of Miami Brain Tumor Initiative, University of Miami Miller School of Medicine, Miami, FL 33136, USA;

关键词: cancer stem cells;    ER stress;    glioblastoma multiforme;    radiation;    unfolded protein response;    autophagy;   

DOI  :  10.3390/cancers11020159

来源: DOAJ

【 摘 要 】

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, and despite optimized treatment options, median survival remains dismal. Contemporary evidence suggests disease recurrence results from expansion of a robustly radioresistant subset of GBM progenitor cells, termed GBM stem cells (GSCs). In this study, we utilized transmission electron microscopy to uncover ultrastructural effects on patient-derived GSC lines exposed to supratherapeutic radiotherapy levels. Elevated autophagosome formation and increased endoplasmic reticulum (ER) internal diameter, a surrogate for ER stress and activation of unfolded protein response (UPR), was uncovered. These observations were confirmed via protein expression through Western blot. Upon interrogating genomic data from an open-access GBM patient database, overexpression of UPR-related chaperone protein genes was inversely correlated with patient survival. This indicated controlled UPR may play a role in promoting radioresistance. To determine if potentiating UPR further can induce apoptosis, we exposed GSCs to radiation with an ER stress-inducing drug, 2-deoxy-D-glucose (2-DG), and found dose-dependent decreases in viability and increased apoptotic marker expression. Taken together, our results indicate GSC radioresistance is, in part, achieved by overexpression and overactivation of ER stress-related pathways, and this effect can be overcome via potentiation of UPR, leading to loss of GSC viability.

【 授权许可】

Unknown