RAGE Up-Regulation Differently Affects Cell Proliferation and Migration in Pancreatic Cancer Cells

Abstract

The receptor for advanced glycation end products (RAGE) contributes to many cellular aspects of pancreatic cancer including cell proliferation, migration, and survival. Studies have shown that RAGE activation by its ligands promotes pancreatic tumor growth by stimulating both cell proliferation and migration. In this study, we investigated the effect of RAGE up-regulation on the proliferation and migration of the human pancreatic cancer Panc-1 cell-line. We show that moderate overexpression of RAGE in Panc-1 cells results in increased cell proliferation, but decreased cell migration. The observed cellular changes were confirmed to be RAGE-specific and reversible by using RAGE-specific siRNAs and the small molecule RAGE inhibitor FPS-ZM1. At the molecular level, we show that RAGE up-regulation was associated with decreased activity of FAK, Akt, Erk1/2, and NF-κB signaling pathways and greatly reduced levels of α2 and β1 integrin expression, which is in agreement with the observed decreases in cell migration. We also demonstrate that RAGE up-regulation changes the expression of key molecular markers of epithelial-to-mesenchymal transition (EMT). Our results suggest that in the absence of stimulation by external ligands, RAGE up-regulation can differently modulate cell proliferation and migration in pancreatic cancer cells and regulates partly EMT.

Proteomic Investigation of Glyceraldehyde-Derived Intracellular AGEs and Their Potential Influence on Pancreatic Ductal Cells

“…Besides AGEs itself, stimulated RAGE expression also contributes to cell proliferation. Overexpression of RAGE in pancreatic cells showed increased cell proliferation, and silencing reduced the RAGE-induced proliferation [ 51 ]. In addition, other cells also showed cell proliferation, corresponding with RAGE expression [ 52 , 53 ].…”

Toxicity of advanced glycation end products (Review)

“…RAGE expression is upregulated in a vast majority of cancers, but its expression is very low under physiological conditions. Specific examples of types of cancer in which RAGE expression is upregulated include colorectal cancer ( 32 ), pancreatic cancer ( 33 ), prostate cancer ( 34 ), lung cancer ( 35 ) and breast cancer, and in breast cancer, it has been reported that the RAGE rs1800624 polymorphism may increase the risk of breast cancer ( 36 ).…”

Pre-Clinical and Clinical Applications of Small Interfering RNAs (siRNA) and Co-Delivery Systems for Pancreatic Cancer Therapy

“…On the other hand, tumor-suppressor factors such as miRNA-573 suppress PC growth via TSPAN1 down-regulation [ 89 ]. Hence, the process of PC growth seems to be complicated and each gene can target various downstream targets to modulate PC progression [ 90 ]. The aim of current section is to show that how siRNAs can be applied in targeting pathways related to the aberrant growth of PC cells.…”