Fig. 2

The roles of AGEs and RAGEs in pancreatic carcinogenesis. The production of AGEs is drastically increased in obesity and DM, and the binding of AGEs to RAGEs activates MAPK and NF-κB signaling and increases the transcription of HIF-1α and NF-κB, which prevents cell death from oxidative stress and creates a hypoxic microenvironment while promoting proinflammatory signaling to exacerbate inflammatory reactions and recruit immunosuppressive MDSCs to diminish anticancer immunity. In addition to the decreased apoptosis due to the decline in the transcription of TP53 following the activation of KRAS signaling, the enhanced PI3K-AKT signaling and the direct activation of mTOR by RAGEs mitigate autophagy to improve the proliferation and survival of cancer cells, thereby promoting pancreatic carcinogenesis. AGEs advanced glycation end products, AKT protein kinase B, DM diabetes mellitus, ERK extracellular signal-regulated kinase, HIF-1α hypoxia-inducible factor 1 subunit α, IKKβ inhibitor of nuclear factor-κB (NF-κB) kinase subunit β, Ikβ inhibitor of NF-κB subunit β, KRAS Kirsten rat sarcoma viral oncogene homolog, MAPK mitogen-activated protein kinase, MDSCs myeloid-derived suppressor cells, MEK mitogen extracellular kinase, mTOR mammalian target of rapamycin, NF-κB nuclear factor-κB, P phosphorylation, PI3K phosphatidylinositol-3-kinase, RAF Raf proto-oncogene, RAGE receptor of AGEs, TP53 tumor suppressor p53