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.
Highlights
Colorectal cancer (CRC) is the third most common cancer in the world and the fourth most common cause of cancer-related deaths [1,2]
In accordance accordance with these observations, in vivo experiments using glyoxalase 1 (GLO1)-depleted HCT116 colon cancer with these observations, in vivo experiments using GLO1-depleted HCT116 colon cancer cells showed cells showed an increased tumor growth associated with MG adducts accumulation that can be an increased tumor growth associated with MG adducts accumulation that can be reverted by carnosine, reverted by carnosine, a potent MG scavenger
Hyperglycemia associated with diabetes is a well-established risk factor of colon cancer and altered glucose metabolism has been recently associated with the development of colorectal adenomas, the pathological precursors of CRC [47]
Summary
Colorectal cancer (CRC) is the third most common cancer in the world and the fourth most common cause of cancer-related deaths [1,2]. The increased glycolytic rate in tumor cells, make them accumulate high levels of reactive dicarbonyl compounds. We demonstrated that triple negative breast cancer cells increased their level of GLO1 expression and activity in response to MG stress while ER/PR positive and HER2 positive cells remained stable under the same conditions. In accordance accordance with these observations, in vivo experiments using GLO1-depleted HCT116 colon cancer with these observations, in vivo experiments using GLO1-depleted HCT116 colon cancer cells showed cells showed an increased tumor growth associated with MG adducts accumulation that can be an increased tumor growth associated with MG adducts accumulation that can be reverted by carnosine, reverted by carnosine, a potent MG scavenger To our knowledge, this is the first study demonstrating a correlation between dicarbonyl stress.
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