The Dual-Role of Methylglyoxal in Tumor Progression – Novel Therapeutic Approaches

Abstract

One of the hallmarks of cancer cells is their metabolic reprogramming, which includes the preference for the use of anaerobic glycolysis to produce energy, even in presence of normal oxygen levels. This phenomenon, known as “Warburg effect”, leads to the increased production of reactive intermediates. Among these Methylglyoxal (MGO), a reactive dicarbonyl known as the major precursor of the advanced glycated end products (AGEs), is attracting great attention. It has been well established that endogenous MGO levels are increased in several types of cancer, however the MGO contribution in tumor progression is still debated. Although an anti-cancer role was initially attributed to MGO due to its cytotoxicity, emerging evidence has highlighted its pro-tumorigenic role in several types of cancer. These apparently conflicting results are explained by the hormetic potential of MGO, in which lower doses of MGO are able to establish an adaptive response in cancer cells while higher doses cause cellular apoptosis. Therefore, the extent of MGO accumulation and the tumor context are crucial to establish MGO contribution to cancer progression. Several therapeutic approaches have been proposed and are currently under investigation to inhibit the pro-tumorigenic action of MGO. In this review, we provide an overview of the early and latest evidence regarding the role of MGO in cancer, in order to define its contribution in tumor progression, and the therapeutic strategies aimed to counteract the tumor growth.

Contributions of Human-Associated Archaeal Metabolites to Tumor Microenvironment and Carcinogenesis

“… Archaeal metabolites and their potential roles with various cancers. Relations were organized and displayed on the basis of previous reports ( 7 , 40 – 42 , 61 , 87 – 89 ). …”

Methylglyoxal Levels in Human Colorectal Precancer and Cancer: Analysis of Tumor and Peritumor Tissue

“…MGO accumulation can promote inflammation and contribute to endothelial dysfunction. The dual-role of MGO in tumor progression and its anti-cancer effect was initially attributed to MGO cytotoxicity, and its subsequent pro-tumorigenic effect was observed in several types of cancer, including CRC [38]. Normal cells use mitochondrial oxidative respiration with oxygen availability to produce energy.…”

Metabolic Rewiring and the Characterization of Oncometabolites

“…MGO irreversibly modifies an estimated 1 to 5% of proteins at arginine residues, forming the MGO-derived argpyrimidine [115] and hydroimidazolone [116] AGEs. The accumulated evidence suggests that MGO-modified proteins connect diabetes with cancer [117] and are associated with several cancers [118]. By silencing the detoxication of MGO by glyoxalase 1, it was reported that MGO favored nuclear localization of the transcriptional coactivator YAP (Yes-associated protein) [119] and inactivation of the Hippo tumor suppressor pathway [120] in breast cancer cells, thereby promoting proliferation [121].…”