Une nouvelle connexion entre le stress dicarbonyle et la régulation épigénétique dans le cancer du sein

Methylglyoxal is a highly reactive compound derived from glycolysis. It can interact with several biological molecules like DNA, lipids or proteins leading to Advanced Glycation Product (AGE). Stress due to MG is known as a cause of several disease. It exists diverse defence mechanisms to regulate dicarbonyl stress and one of the most important is the Glyoxalase system composed of Glo1 and Glo2 enzymes. Epigenetic disorders are correlated with many human diseases including carcinogenesis. Aberrant DNA methylation or demethylation has been recognized as common molecular alterations in human neoplasia. To better understand the connexion between epigenetic disorders, metastatic properties and MG dicarbonyl stress in breast cancer, we used MDA-MB-231 cell line stably depleted for Glo1 to create an endogenous MG stress model. In this in vitro model, we observed the presence of a pro-metastatic signature under MG stress and a hypermethylation of the genome that was correlated with an increase of a de novo DNA methyltransferase (DNMT3A) protein expression. Interestingly, we could reverse DNMT3A over-expression via the use of MG scavengers like carnosine. As a perspective, we consider to investigate the MG stress-induce migratory capacities through the inhibition of DNMTs

Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab

The use of cetuximab anti-epidermal growth factor receptor (anti-EGFR) antibodies has opened the era of targeted and personalized therapy in colorectal cancer (CRC). Poor response rates have been unequivocally shown in mutant KRAS and are even observed in a majority of wild-type KRAS tumors. Therefore, patient selection based on mutational profiling remains problematic. We previously identified methylglyoxal (MGO), a by-product of glycolysis, as a metabolite promoting tumor growth and metastasis. Mutant KRAS cells under MGO stress show AKT-dependent survival when compared with wild-type KRAS isogenic CRC cells. MGO induces AKT activation through phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin 2 (mTORC2) and Hsp27 regulation. Importantly, the sole induction of MGO stress in sensitive wild-type KRAS cells renders them resistant to cetuximab. MGO scavengers inhibit AKT and resensitize KRAS-mutated CRC cells to cetuximab in vivo. This study establishes a link between MGO and AKT activation and pinpoints this oncometabolite as a potential target to tackle EGFR-targeted therapy resistance in CRC.Role of methylglyoxal stress in the resistance of KRAS mutated human colon cancer to targeted therap