title: The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia.
abstract: Pancreatic cancer is an almost uniformly lethal disease, characterized by late diagnosis, early metastasis, resistance to chemotherapy, and early mutation of the Kras oncogene. Here we show that the receptor for advanced glycation endproducts (RAGE) is required for the activation of interleukin 6 (IL-6)-mediated mitochondrial signal transducers and activators of transcription 3 (STAT3) signaling in pancreatic carcinogenesis. RAGE expression correlates with elevated levels of autophagy in pancreatic cancer in vivo and in vitro, and this heightened state of autophagy is required for IL-6-induced STAT3 activation. To further explore the intersection of RAGE, autophagy, and pancreatic carcinogenesis, we created a transgenic murine model, backcrossing RAGE-null mice to a spontaneous mouse model of pancreatic cancer, Pdx1-Cre:Kras(G12D/+) (KC). Targeted ablation of Rage in KC mice delayed neoplasia development, decreased levels of autophagy, and inhibited mitochondrial STAT3 activity and subsequent ATP production. Our results suggest a critical role for RAGE expression in the earliest stages of pancreatic carcinogenesis, potentially acting as the "autophagic switch," regulating mitochondrial STAT3 signaling.
authors.affiliation: Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15219, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.forename: Tara
authors.initials: T
authors.lastname: Loux
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Schapiro
authors.forename: Philip
authors.initials: P
authors.lastname: Vernon
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Livesey
authors.forename: Alyssa
authors.initials: A
authors.lastname: Krasinskas
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Zeh
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001343:Autophagy; D045744:Cell Line, Tumor; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology / Q000502:physiology
chemical_list: D015850:Interleukin-6; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D050796:STAT3 Transcription Factor; D000255:Adenosine Triphosphate; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)