Targeting glioblastoma stem cells with 2-deoxy-d-glucose (2-DG) potentiates radiation-induced unfolded protein response (UPR)

Sumedh S. Shah, Gregor A. Rodriguez, Alexis Musick, Winston M. Walters, Nicolas de Cordoba, Eric Barbarite, Megan M. Marlow, Brian Marples, Jeffrey S. Prince, Ricardo J. Komotar, Steven Vanni, Regina M. Graham

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number159
JournalCancers
Volume11
Issue number2
DOIs
StatePublished - Feb 1 2019

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Unfolded Protein Response
Glioblastoma
Stem Cells
Radiation
Glucose
Endoplasmic Reticulum Stress
Survival
Deoxyglucose
Transmission Electron Microscopy
Brain Neoplasms
Endoplasmic Reticulum
Cell Survival
Proteins
Radiotherapy
Western Blotting
Databases
Apoptosis
Recurrence
Cell Line
Pharmaceutical Preparations

Keywords

  • Autophagy
  • Cancer stem cells
  • ER stress
  • Glioblastoma multiforme
  • Radiation
  • Unfolded protein response

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Targeting glioblastoma stem cells with 2-deoxy-d-glucose (2-DG) potentiates radiation-induced unfolded protein response (UPR). / 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.

In: Cancers, Vol. 11, No. 2, 159, 01.02.2019.

Research output: Contribution to journalArticle

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. / Targeting glioblastoma stem cells with 2-deoxy-d-glucose (2-DG) potentiates radiation-induced unfolded protein response (UPR). In: Cancers. 2019 ; Vol. 11, No. 2.
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AB - 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.

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