The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia

Rui Kang, Tara Loux, Daolin Tang, Nicole E. Schapiro, Philip Vernon, Kristen M. Livesey, Alyssa Krasinskas, Michael T. Lotze, Herbert J. Zeh

Research output: Contribution to journalArticle

87 Scopus citations

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:KrasG12D/+(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.

Original languageEnglish (US)
Pages (from-to)7031-7036
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number18
DOIs
StatePublished - May 1 2012

Keywords

  • Bioenergetics
  • High-mobility group box 1
  • Inflammation
  • Metabolism
  • Oncogenesis

ASJC Scopus subject areas

  • General

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