Effect of Hypoxia on RAGE Signaling in Pancreatic Cancer

Pancreatic cancer (PC) is one of the deadliest cancers owing to its late diagnostic and poor response to chemotherapeutic agents. PC tumors are characterized by large hypoxic regions that contribute to tumor growth, formation of metastasis and resistance to chemotherapeutic agents. Studies have shown that the Receptor for Advanced Glycation End products (RAGE) is upregulated in hypoxic conditions. The goal of this study was to determine the effect of hypoxia on RAGE signaling in two pancreatic cancer cell lines (Panc‐1 and CFPAC). In particular we investigated if hypoxia dependent RAGE upregulation could aftect RAGE signaling and lead to NF‐κB activation. To interrogate RAGE signaling, we first investigated the effect of hypoxia on KRAS upregulation, as well as on ERK and NF‐KB activity levels by Western blot analysis. We use cobalt chloride to create hypoxic‐like conditions by stabilizing HIF‐1α in cells. We confirmed up‐regulation of HIF‐1α and RAGE in cells incubated with cobalt chloride. We also observed increased expression levels of KRAS in hypoxic‐like conditions. Additionally, higher levels of NF‐κB (p65) and of phosphorylated ERK were observed in cells treated with cobalt chloride as compared to untreated cells. In many cell types, RAGE signaling leads to NF‐κB activation resulting in further RAGE upregulation through a feedforward mechanism. Based on these observations, we hypothesize that in hypoxic conditions, stabilization of HIF‐1α leads to RAGE upregulation and signaling, resulting in NF‐κB activation through the activation of KRAS and ERK. We will use a small molecule RAGE inhibitor (FPS‐ZM1) to interrogate the role of RAGE in the proposed KRAS/ERK/NF‐κB pathway. Support or Funding Information Department of Pharmaceutical Sciences, College of Health Professions, NDSU, NIH‐COBRE: P20GM109024