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

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.

LncRNA OIP5-AS1 Promotes Breast Cancer Progression by Regulating miR-216a-5p/GLO1

“…For example, GLO1 was upregulated in hepatocellular carcinoma, and GLO1 knockdown depleted cell proliferation. 19 The situation of GLO1 in multiple myeloma, 20 prostate cancer, 21 and brain tumor 22 was consistent with that in hepatocellular carcinoma. 19 These data imply that GLO1 is indeed a tumor supporter in diverse cancers.…”

Identification of Crucial Candidate Genes and Pathways in Glioblastoma Multiform by Bioinformatics Analysis

“…Polymorphism in tumor suppressor RPL14 was associated with the pathogenesis of lung and oral cancers [88], but this polymorphic gene may be responsible for the growth of GBM. Genes such as RPL34 [89], GLO1 [90], LDHB [91], and COX5B [92] were responsible for pathogenesis of GBM. RPL41 , RPL36A , MRPL30 , MRPL35 , MRPS17 , MRPL20 , RPL26L1 , MRPS31 , MRRF, MRPL58 , MRPL40 , NDUFA9 , and ATP6V0D2 were identified as novel biomarkers for the pathogenesis of GBM.…”

Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases

“…As mentioned above, MGO plays an important role in the process of apoptosis and cell death (101,151,420), and a reduction of intracellular MGO by high Glo1 expression is likely the mechanism to explain the survival-promoting effects of high Glo1 expression. MGO can induce apoptosis in cancer cells through generation of ROS and GSH depletion (21), inhibition of cellular respiration (193), DNA modification and DNA-protein cross-link resulting in DNA instability (259,556,632), negative regulation of anti-apoptotic proteins Bcl-2 as well as positive regulation of pro-apoptotic proteins (30,341,557), and impaired mitochondrial permeability via the modification of mitochondrial proteins and release of cytochrome c (539). Thus increased expression of Glo1 plays a crucial role in the survival and proliferation of tumor cells by lowering MGO concentrations.…”