TY - JOUR
T1 - The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia
AU - Kang, Rui
AU - Loux, Tara
AU - Tang, Daolin
AU - Schapiro, Nicole E.
AU - Vernon, Philip
AU - Livesey, Kristen M.
AU - Krasinskas, Alyssa
AU - Lotze, Michael T.
AU - Zeh, Herbert J.
PY - 2012/5/1
Y1 - 2012/5/1
N2 - 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.
AB - 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.
KW - Bioenergetics
KW - High-mobility group box 1
KW - Inflammation
KW - Metabolism
KW - Oncogenesis
UR - http://www.scopus.com/inward/record.url?scp=84860813449&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84860813449&partnerID=8YFLogxK
U2 - 10.1073/pnas.1113865109
DO - 10.1073/pnas.1113865109
M3 - Article
C2 - 22509024
AN - SCOPUS:84860813449
SN - 0027-8424
VL - 109
SP - 7031
EP - 7036
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 18
ER -