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Open AccessArticle

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

1
University of Miami Brain Tumor Initiative, University of Miami Miller School of Medicine, Miami, FL 33136, USA
2
Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
3
Dauer Electron Microscopy Laboratory, Department of Biology, University of Miami, Coral Gables, FL 33146, USA
4
Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
5
Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL 33136, USA
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(2), 159; https://doi.org/10.3390/cancers11020159
Received: 1 January 2019 / Revised: 24 January 2019 / Accepted: 29 January 2019 / Published: 31 January 2019
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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. View Full-Text
Keywords: cancer stem cells; ER stress; glioblastoma multiforme; radiation; unfolded protein response; autophagy cancer stem cells; ER stress; glioblastoma multiforme; radiation; unfolded protein response; autophagy
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Shah, S.S.; Rodriguez, G.A.; Musick, A.; Walters, W.M.; de Cordoba, N.; Barbarite, E.; Marlow, M.M.; Marples, B.; Prince, J.S.; Komotar, R.J.; Vanni, S.; Graham, R.M. Targeting Glioblastoma Stem Cells with 2-Deoxy-D-Glucose (2-DG) Potentiates Radiation-Induced Unfolded Protein Response (UPR). Cancers 2019, 11, 159.

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