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Int. J. Mol. Sci. 2018, 19(2), 406; https://doi.org/10.3390/ijms19020406

Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models

1
Division of Neurosurgery, City of Hope & Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010, USA
2
Department of Neurosurgery, Keck School Medicine, University of Southern California, 1975 Zonal Ave., Los Angeles, CA 90033, USA
3
Department of Molecular Medicine, City of Hope & Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010, USA
4
Irell and Manella Graduate School of Biological Sciences, City of Hope & Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010, USA
5
Department of Chemistry and Biochemistry, California State University, Northridge, 18111 Nordhoff Street, Northridge, CA 91330, USA
6
Department of Chemistry, Texas A&M University, PO Box 30012, College Station, TX 77842, USA
7
Center for Informatics, City of Hope & Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010, USA
*
Author to whom correspondence should be addressed.
Received: 23 December 2017 / Revised: 22 January 2018 / Accepted: 26 January 2018 / Published: 30 January 2018
(This article belongs to the Special Issue Glyoxalase System in Health and Disease 2017)
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Abstract

Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA) approaches. Inhibition of GLO1 with S-(p-bromobenzyl) glutathione dicyclopentyl ester (p-BrBzGSH(Cp)2) increased levels of the DNA-AGE N2-1-(carboxyethyl)-2′-deoxyguanosine (CEdG), a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE); and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p-BrBzGSH(Cp)2 exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors. View Full-Text
Keywords: glyoxalase 1; AGEs; RAGE; methylglyoxal; CEdG glyoxalase 1; AGEs; RAGE; methylglyoxal; CEdG
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Jandial, R.; Neman, J.; Lim, P.P.; Tamae, D.; Kowolik, C.M.; Wuenschell, G.E.; Shuck, S.C.; Ciminera, A.K.; De Jesus, L.R.; Ouyang, C.; Chen, M.Y.; Termini, J. Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models. Int. J. Mol. Sci. 2018, 19, 406.

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