AGER/RAGE-mediated autophagy promotes pancreatic tumorigenesis and bioenergetics through the IL6-pSTAT3 pathway.
Pancreatic ductal adenocarcinoma (PDA), the fourth leading cause of cancer death in the United States, is a complex disease that arises in the setting of genetic alterations (KRAS, BRCA1, SMAD4, CDKN2A/p16 (INK4a)  and TP53), epigenetic perturbations (MIR155, acetylation and methylation) and epicellular events (diabetes and inflammation). We have demonstrated that the advanced glycation end product-specific receptor (AGER, also called RAGE) contributes to pancreatic tumorigenesis. Targeted ablation of AGER diminishes the amount of autophagic flux and attenuates the development of early pancreatic intraepithelial neoplasia (PanIN) lesions in a murine model of KRAS-drivien carcinogenesis. Autophagy (programmed cell survival), a metabolic process of lysosome-mediated self-digestion, promotes pancreatic cancer growth. In pancreatic tumor cell lines, AGER-mediated autophagy promotes interleukin-6 (IL6)-induced phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) and mitochondrial localization of pSTAT3. Enhanced mitochondrial pSTAT3 increases the pool of available ATP and increases cellular proliferation. Moreover, we observed a positive feedback loop between activation of autophagy and the IL6-pSTAT3 pathway, perhaps different from the role of cytosolic nonphosphorylated STAT3, which has been reported to inhibit autophagy. These AGER-dependent changes were found during the earliest stages of pancreatic cancer development. These observations of inflammation and altered metabolism in PDA provide a pathological link to early precursor lesion development. Thus, AGER is an important inflammatory mediator that modulates crosstalk between prosurvival pathways, IL6-pSTAT3 and autophagy, in PDA tumor cells, and contributes to early PanIN formation.
The DAMP Laboratory, Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
Rui
R
Kang
Daolin
D
Tang
Michael T
MT
Lotze
Herbert J
HJ
Zeh
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001343:Autophagy; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004195:Disease Models, Animal; D004734:Energy Metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
D015850:Interleukin-6; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D050796:STAT3 Transcription Factor; D000255:Adenosine Triphosphate