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.oncogenesis | bioenergetics | inflammation | metabolism | high-mobility group box 1 P ancreatic cancer ranks as the fourth leading cause of cancer death, accounting for 6-7% of all cancer-related deaths in the United States, in 2011 (1). Most pancreatic ductal adenocarcinomas (PDA) are thought to arise from well-defined precursor lesions, termed pancreatic ductal intraepithelial neoplasia (PanIN) (2). Many human PanIN lesions do not progress to invasive carcinomas, so defining the events that drive carcinogenesis in the emergent tumor microenvironment is of critical importance. Studies into human pancreatic carcinogenesis have been greatly facilitated by the development of a genetically engineered mouse model that expresses oncogenic Kras under a pancreatic promoter Pdx1-Cre:Kras G12D/+ (KC) (3). A more detailed understanding of how these pathways accelerate pancreatic carcinogenesis may allow improved therapeutic strategies.The receptor for advanced glycation endproducts (RAGE) is a member of the Ig superfamily. RAGE and its ligands, including high-mobility group box 1 (HMGB1) and S100, are linked to the development and progression of several cancers by facilitating the maintenance of a chronic inflammatory state (4) and/or by promotion of metastases (5). We previously observed that RAGE sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival during chemotherapy and oxidative stress in vivo and in vitro (6, 7). Autophagy is an essential catabolic process by which cells break down old or damaged organelles and proteins (8). Autophagy promotes cell survival and supports metabolism during cell stress (9). Conversely, apoptosis promotes tumor growth early in the development of cancer (10) during periods of inhibition of autophagy with a subsequent switch to suppressed apoptosis, acquired later...

Eat-Me: Autophagy, Phagocytosis, and Reactive Oxygen Species Signaling

“…The induction of autophagy by both intracellular and extracellular HMGB1 is important for tumor development and a novel target for cancer therapy (50,68,113,124). In addition, its receptor RAGE also regulates autophagy in pancreatic cancer cells (53)(54)(55). Targeted ablation of RAGE in mice delays pancreatic tumorigenesis and inhibits IL-6/STAT3-mediated autophagy (53).…”

Extracellular HMGB1 promotes differentiation of nurse-like cells in chronic lymphocytic leukemia

“…13,24 RAGE is a critical mediator of pancreatic carcinogenesis through its ability to amplify interleukin (IL)-6-induced autophagic translocation of signal transducer and activator of transcription (STAT)3 to the mitochondria and enhance ATP production. 25 Blockade of HMGB1 and RAGE suppressed tumor growth and metastasis in a murine model of lung cancer. 26 As an intracellular receptor for DNA, TLR9 activation by an endogenous proteinnucleic acid complex plays an important role in autoimmune disease 21,27 and also confers CLL cell resistance to fludarabine treatment.…”

An Advanced Glycation End Product (AGE)-Receptor for AGEs (RAGE) Axis Restores Adipogenic Potential of Senescent Preadipocytes through Modulation of p53 Protein Function

“…An inhibitory function of RAGE in p53 expression and p53 function has been reported in tumor and osteoblastic cells (51,52). In line with this, RAGE has been recently proposed to regulate both autophagy and apoptosis (53)(54)(55). Additionally, RAGE knockdown has been shown to lower degradation and ubiquitination of p53, thereby promoting its nuclear translocation in murine osteoblastic cells (52).…”