Methylglyoxal-Mediated Stress Correlates with High Metabolic Activity and Promotes Tumor Growth in Colorectal Cancer

Abstract

Cancer cells generally rely on aerobic glycolysis as a major source of energy. Methylglyoxal (MG), a dicarbonyl compound that is produced as a side product during glycolysis, is highly reactive and induces the formation of advanced glycation end-products that are implicated in several pathologies including cancer. All mammalian cells have an enzymatic defense against MG composed by glyoxalases GLO1 and GLO2 that converts MG to d-lactate. Colorectal cancer (CRC) is one of the most frequently occurring cancers with high morbidity and mortality. In this study, we used immunohistochemistry to examine the level of MG protein adducts, in a series of 102 CRC human tumors divided into four clinical stages. We consistently detected a high level of MG adducts and low GLO1 activity in high stage tumors compared to low stage ones suggesting a pro-tumor role for dicarbonyl stress. Accordingly, GLO1 depletion in CRC cells promoted tumor growth in vivo that was efficiently reversed using carnosine, a potent MG scavenger. Our study represents the first demonstration that MG adducts accumulation is a consistent feature of high stage CRC tumors. Our data point to MG production and detoxification levels as an important molecular link between exacerbated glycolytic activity and CRC progression.

Blockage of Glyoxalase I Inhibits Colorectal Tumorigenesis and Tumor Growth via Upregulation of STAT1, p53, and Bax and Downregulation of c-Myc and Bcl-2

“…In contrast, a recent study found tumors high-stage CRCs with low GLOI expression expression and enzymatic activity when compared with low stage [30]. However, GLOI activity was not compared to the normal tissue in this study.…”

ERN1 modifies the effect of glutamine deprivation on tumor growth related factors expression in U87 glioma cells

“…Thus, this enzyme is implicated in the progression of human malignancies and is up-regulated in tumor tissues with high metabolic rate [31]. At the same time, there is data that the activity of GLO1 in high stage colorectal cancer is lower compared to low stage ones [32]. Furthermore, knockdown of GLO1 in the cancer cells significantly reduced tumor-associated properties such as migration and proliferation, whereas hypoxia caused inhibition of cell growth of all cells except of those over-expressing GLO1 [33].…”

Metabolism in cancer metastasis: bioenergetics, biosynthesis, and beyond

“…Besides lactate, methylglyoxal (MG), a glycolytic side‐product, has been shown to promote metastasis by reacting with the molecular chaperone Hsp90 through glycation, which disrupts the Hippo signaling pathway and permits transcriptional activation of oncogenes such as c‐Myc by Yes‐associated protein . Although increased metastasis is seen with MG addition or knockdown of MG‐detoxifying glyoxalase (GLO1), this may be simply due to increased tumor cell growth and proliferation …”