Hormetic potential of methylglyoxal, a side-product of glycolysis, in switching tumours from growth to death

Abstract

Metabolic reprogramming toward aerobic glycolysis unavoidably favours methylglyoxal (MG) and advanced glycation end products (AGEs) formation in cancer cells. MG was initially considered a highly cytotoxic molecule with potential anti-cancer value. However, we have recently demonstrated that MG enhanced tumour growth and metastasis. In an attempt to understand this dual role, we explored MG-mediated dicarbonyl stress status in four breast and glioblastoma cancer cell lines in relation with their glycolytic phenotype and MG detoxifying capacity. In glycolytic cancer cells cultured in high glucose, we observed a significant increase of the conversion of MG to D-lactate through the glyoxalase system. Moreover, upon exogenous MG challenge, glycolytic cells showed elevated amounts of intracellular MG and induced de novo GLO1 detoxifying enzyme and Nrf2 expression. Thus, supporting the adaptive nature of glycolytic cancer cells to MG dicarbonyl stress when compared to non-glycolytic ones. Finally and consistent with the pro-tumoural role of MG, we showed that low doses of MG induced AGEs formation and tumour growth in vivo, both of which can be reversed using a MG scavenger. Our study represents the first demonstration of a hormetic effect of MG defined by a low-dose stimulation and a high-dose inhibition of tumour growth.

Methylglyoxal-derived posttranslational arginine modifications are abundant histone marks

“…3 D ) PTMs on chromatin fractions. A significant elevation in acetylated Lys (acLys) was observed following hyperglycemia, consistent with previous reports ( 24 ). In addition, a significant increase in CEA was observed following hyperglycemia; however, no such increase was observed with MG-H1 or CEL adducts ( Fig.…”

“…Nonetheless, despite these global alterations in gene expression, no clear pathway enrichment was observed. Although nonhistone proteins are also known to be modified by MGO ( 24 , 39 ), these data support the idea that MGO forms PTMs that play an active role in the regulation of gene expression, rather than simply serving as a reactive molecule responsible for the induction of electrophile-response pathways ( 40 ).…”

Cancer Cell Metabolism Bolsters Immunotherapy Resistance by Promoting an Immunosuppressive Tumor Microenvironment

“…Methylglyoxal (MG), a by-product of glycolysis, is present ubiquitously in living cells ( 109 – 111 ). MG induces the production of advanced glycation end products and promotes tumor proliferation in vivo ( 112 , 113 ). Because tumors exhibit high rates of aerobic glycolysis, enhanced aerobic glycolysis in tumors leads to the accumulation of MG in the TME, raising concerns about the role of MG in promoting immune evasion.…”

Genetic Target Modulation Employing CRISPR/Cas9 Identifies Glyoxalase 1 as a Novel Molecular Determinant of Invasion and Metastasis in A375 Human Malignant Melanoma Cells In Vitro and In Vivo

“…Glyoxalase 1 (encoded by GLO1; NM_006708) is a glutathione-dependent enzyme involved in the detoxification of the reactive glycolytic byproduct methylglyoxal (by catalyzing the formation of S-lactoyl-glutathione from methylglyoxal and reduced glutathione) [ 1 , 2 ]. Recent interest has focused on the emerging role of methylglyoxal and (R)-S-Lactoylglutathione as cellular oncometabolites, involved in tumorigenesis-associated metabolic reprogramming, redox dysregulation, and epigenetic recoding that occurs as a result of posttranslational adduction targeting specific proteins including histones [ 3 , 4 , 5 , 6 , 7 ]. Further, a role of GLO1 in cancer cell chemoresistance has been demonstrated, and the development of pharmacological and genetic strategies modulating GLO1 for experimental cancer therapy has attracted significant attention [ 8 , 9 , 10 , 11 , 12 ].…”