Effect of Hypoxia on RAGE Dependent Migration in Pancreatic Cancer Cells

Abstract

Pancreatic cancer (PC) is one of the deadliest cancers owing to its late diagnosis and chemoresistance. PC tumors are characterized by large hypoxic regions that contribute to cell proliferation and migration, tumor growth, formation of metastases and resistance to chemotherapeutic agents. Studies have shown that the Receptor for Advanced Glycation End products (RAGE) is upregulated in hypoxic conditions. In addition, RAGE has been shown to activate NF‐κB, resulting in the transcription of genes involved in cancer cell migration. The goal of our study was to determine if, under hypoxic conditions, RAGE promotes migration of pancreatic cancer cells via NF‐κB. We performed our study in hypoxic like conditions using cobalt chloride as HIF‐1α stabilizer. The generation of hypoxic‐like conditions was determined by comparing the levels of HIF‐1α in the absence and presence of cobalt chloride, by Western blot analysis and immunofluorescence. The levels of RAGE and the p65 subunit of NF‐κB was determined by Western blot analysis as well. Cell migration was assessed using Boyden chamber assays. As anticipated, higher levels of HIF‐1α were observed in hypoxic‐like conditions than in normoxia.RAGE and p65 expression levels were also found to be higher in hypoxic‐like conditions than in normoxia.At the cellular level, we found that a larger number of cells had migrated through the filter in the presence than in the absence of cobalt chloride. We are currently investigating how blocking RAGE activity affects the migration of pancreatic cancer cells in hypoxic‐like conditions.

Hypoxia-induced HMGB1 promotes glioma stem cells self-renewal and tumorigenicity via RAGE

“…The engagement of RAGE and its ligands triggers signaling pathway cascade including ERK, PI3K/AKT, and Jak/STAT pathways (Oh et al, 2018;Kang et al, 2014b;Taneja et al, 2021). ERK binds intracellularly to the cytoplasmic domain of RAGE (Ishihara et al, 2003), integrating external signals into signaling events promoting cell growth and proliferation in many cell types including glioma cells (Huang et al, 2018;Tang et al, 2021;Wang et al, 2019).…”