Fig. 8

Carbonyl stress in PaC promotion induced by diabetes and mechanism of FL-926-16-mediated protection. Diabetes markedly accelerates tumour progression through hyperglycaemia-derived carbonyl stress. The increased availability of glucose feeds the glycolytic flux of tumour cells favouring local formation of RCS such as MGO, an inevitable side-product of glycolysis, and consequent AGE accumulation. In addition, circulating RCS and their protein adducts (i.e., AGEs) derived from non-enzymatic glycoxidation reactions occurring at the systemic level may also contribute to AGE accumulation in neoplastic lesions, which is associated with increased nuclear translocation of YAP, a key effector of Hippo pathway and regulator of tumour growth and invasion [24, 25, 34, 37]. Quenching of RCS and inhibition of AGE formation by the RCS sequestering agent FL-926-16 efficiently prevents hyperglycaemia-induced YAP activation and acceleration of PanIN progression to invasive PaC. LATS1 = large tumour suppressor kinase 1; ERK = extracellular signal-regulated kinase; p-EGFR = phosphorylated epidermal growth factor receptor; p-YAP = phosphorylated YAP