Hypoxia driven glycation: Mechanisms and therapeutic opportunities

Abstract

Tumor masses are deprived of oxygen and characterized by enhanced glucose uptake followed by glycolysis. Elevated glucose levels induce non-enzymatic glycosylation or glycation of proteins which leads to accumulation of advanced glycation end products (AGE). These AGE molecules bind to their respective receptors called the receptor for advanced glycation end products (RAGE) and initiate several aberrant signaling pathways leading to onset of diseases such as diabetes, Alzheimer's, atherosclerosis, heart failure and cancer. The role of AGE in cancer progression is being extensively studied in recent years. As cancer cells are hypoxic in nature and adapted to glycolysis, which induces glycation, its effects need to be understood in greater detail. Since AGE-RAGE signaling is involved in cancer progression, inhibition of AGE-RAGE interaction could be a potential therapeutic target. The purpose of this review is to highlight the role of AGE-RAGE interaction in hypoxic cancer cells.

Keywords: Advanced glycation end products; Cancer; Glycation; Hif1α; Hypoxia; RAGE.

Figure 1. Schematic presentation of the Maillard reaction

Amino group of protein (arginine and lysine derivatives) react with carbonyl moiety of reducing sugars to form reversible Schiff base which further rearranges to form Amadori products. These products finally form Advanced Glycation End Products (AGE) through dicarbonyl intermediates.

Figure 2. Structure of receptor for advanced glycation end product (RAGE)

The RAGE is composed of three extracellular immunoglobulin (Ig)-like domains, a single transmembrane helix (light pink) and a short cytoplasmic (dark sky blue) domain. The Ig domains are V (shown in dark green), C1 (orange) and C2 domain (dark brown). The V-domain is responsible for binding to the AGE (faint blue) and cytoplasmic tail responses to the signaling pathways.

Figure 3. Hypoxia-induced AGE-RAGE-mediated signaling pathways

Hypoxia induces AGE accumulation which further formed complex with RAGE and activates several downstream pathways including NF-Kb, Hif1α, ERK and AKT signaling. These pathways further contribute to cancer metastasis progression.

Figure 4. Hypoxia-driven AGE-RAGE-mediated carcinogenesis is induced by Hif1α

Hypoxic microenvironment induces glycolysis and dicarbonyls accumulation. These dicarbonyls further trigger AGE generation. Once AGE interact with their receptors, RAGE, they activate Hif1α signaling pathways which further act as a transcription factor for synthesis of cell survival and metastasis related genes.