The Receptor for Advanced Glycation End-Products (RAGE) Protects Pancreatic Tumor Cells Against Oxidative Injury

Abstract

Reactive oxygen species, including hydrogen peroxide (H 2 O 2 ), can cause toxicity and act as signaling molecules in various pathways regulating both cell survival and cell death. However, the sequence of events between the oxidative insult and cell damage remains unclear. In the current study, we investigated the effect of oxidative stress on activation of the Receptor for Advanced Glycation End-products (RAGE) and subsequent protection against H 2 O 2 -induced pancreatic tumor cell damage. We found that exposure of pancreatic tumor cells to H 2 O 2 provoked a nuclear factor kappa B (NF-kB)-dependent increase in RAGE expression. Further, suppression of RAGE expression by RNA interference increased the sensitivity of pancreatic tumor cells to oxidative injury. Furthermore, targeted knockdown of RAGE led to increased cell death by apoptosis and diminished cell survival by autophagy during H 2 O 2 -induced oxidative injury. Moreover, we demonstrate that RAGE is a positive feedback regulator for NF-kB as knockdown of RAGE decreased H 2 O 2 -induced activity of NF-kB. Taken together, these results suggest that RAGE is an important regulator of oxidative injury. Antioxid. Redox Signal. 15, 2175-2184.

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

“…2A). Consistent with our previous observations in vitro (6,7), targeted ablation of RAGE decreased levels of autophagy [microtubule-associated protein light chain 3 (LC3)] in PanIN lesions ( Fig. 2B and Fig.…”

“…Our previous studies have demonstrated that RAGE is a positive regulator of autophagy during chemotherapy and oxidative stress (6,7). Consistent with these observations, we found that knockdown of RAGE in pancreatic cancer cells decreased IL-6 and STAT3 cDNA-induced conversion of LC3-I to LC3-II (Fig.…”

“…Inhibition of autophagy in pancreatic tumor cells augments production of reactive oxygen species, increases DNA damage, and limits effective metabolism with decreased mitochondrial oxidative phosphorylation, resulting in significant inhibition of pancreatic tumor growth (12). Despite the growing body of literature supporting the importance of autophagy and RAGE in pancreatic cancer (6,7,12), the role of RAGE-mediated autophagy in pancreatic carcinogenesis and the underlying mechanisms for such a phenomenon have not been addressed.We demonstrate here that RAGE expression is permissive for the development of early pancreatic neoplasia by enhancing the mitochondrial interleukin 6 (IL-6)/signal transducers and activators of transcription 3 (STAT3) pathway in pancreatic tumor cells. These effects depend on autophagy and lead to enhanced ATP production in vitro and in vivo.…”

“…Inhibition of autophagy in pancreatic tumor cells augments production of reactive oxygen species, increases DNA damage, and limits effective metabolism with decreased mitochondrial oxidative phosphorylation, resulting in significant inhibition of pancreatic tumor growth (12). Despite the growing body of literature supporting the importance of autophagy and RAGE in pancreatic cancer (6,7,12), the role of RAGE-mediated autophagy in pancreatic carcinogenesis and the underlying mechanisms for such a phenomenon have not been addressed.…”

“…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).…”