Tumor cells require increased adenosine triphosphate (ATP) to support anabolism and proliferation. The precise mechanisms regulating this process in tumor cells are unknown. Here, we show that the receptor for advanced glycation endproducts (RAGE) and one of its primary ligands, high-mobility group box 1 (HMGB1), are required for optimal mitochondrial function within tumors. We found that RAGE is present in the mitochondria of cultured tumor cells as well as primary tumors. RAGE and HMGB1 coordinately enhanced tumor cell mitochondrial complex I activity, ATP production, tumor cell proliferation and migration. Lack of RAGE or inhibition of HMGB1 release diminished ATP production and slowed tumor growth in vitro and in vivo. These findings link, for the first time, the HMGB1–RAGE pathway with changes in bioenergetics. Moreover, our observations provide a novel mechanism within the tumor microenvironment by which necrosis and inflammation promote tumor progression.
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...
Pancreatic ductal adenocarcinoma (PDA) has an aggressive natural history and is resistant to therapy. The receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor for many damage associated molecular pattern (DAMP) molecules. RAGE is overexpressed in both human and murine models of PDA as well as most advanced epithelial neoplasms. The immunosuppressive nature of the PDA micro-environment is facilitated, in part, by the accumulation of regulatory immune cell infiltrates such as myeloid-derived suppressor cells (MDSCs). To study the role of RAGE expression in the setting of mutant Ras-promoted pancreatic carcinogenesis (KC), a triple transgenic model of spontaneous murine PDA in a RAGE-null background (KCR) was generated. KCR mice had markedly delayed pancreatic carcinogenesis and a significant diminution of MDSCs compared to KC mice at comparable time points post weaning. While RAGE was not required for the development or suppressor activity of MDSCs, its absence was associated with temporally limited pancreatic neoplasia and altered phenotype and function of the myeloid cells. In lieu of MDSCs, KCR animals at comparable time points exhibited mature CD11b+Gr1−F4/80+ cells which were not immunosuppressive in vitro. KCR mice also maintained a significantly less suppressive milieu evidenced by marked decreases in CCL22 in relation to CXCL10 and diminished serum levels of IL-6.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.