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

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 GB...

Full description

Saved in:
Bibliographic Details
Published in:Cancers 2019-01, Vol.11 (2), p.159
Main Authors: Shah, Sumedh S, Rodriguez, Gregor A, Musick, Alexis, Walters, Winston M, de Cordoba, Nicolas, Barbarite, Eric, Marlow, Megan M, Marples, Brian, Prince, Jeffrey S, Komotar, Ricardo J, Vanni, Steven, Graham, Regina M
Format: Article
Language:English
Subjects:
Apoptosis
Autophagy
Brain cancer
Brain tumors
Cancer therapies
DNA damage
Drug dosages
Endoplasmic reticulum
Glioblastoma
Glucose
Homeostasis
Hypotheses
Microscopy
Morphology
Phosphorylation
Progenitor cells
Protein folding
Proteins
Radiation therapy
Radioresistance
Stem cells
Transmission electron microscopy
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers11020159