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

Priyanka Swami,Estelle Leclerc,Arianna Vidger,Venkata S K Indurthi,Stefan W Vetter,Swetha Thiyagarajan

doi:10.3390/ijms21207723

Priyanka Swami, Estelle Leclerc + Show 4 more

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https://doi.org/10.3390/ijms21207723

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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.

Highlights

The receptor for advanced glycation end products (RAGE) is an immunoglobulin-like cell surface receptor involved in cancer, complications of diabetes, and neurodegenerative disorders [1,2,3,4]
RAGE is described as a receptor for damage-associated molecular patterns (DAMPs) because many RAGE ligands are associated with tissue damage, inflammatory or metabolic stress [5,6,7,8,9]
Our study shows that RAGE up-regulation increases cell proliferation and reduces the migration properties of the human pancreatic cancer Panc-1 cell-line

Summary

Introduction

The receptor for advanced glycation end products (RAGE) is an immunoglobulin-like cell surface receptor involved in cancer, complications of diabetes, and neurodegenerative disorders [1,2,3,4]. RAGE is activated by several groups of unrelated ligands including advanced glycation end products (AGE), S100 proteins, amyloid β peptides, as well as DNA and glycosaminoglycans. RAGE is normally expressed at low levels in most healthy tissues, exceptions being embryonic tissues and adult lung tissue [10]. RAGE expression is higher in diseased human tissues including tumors (brain, brain, colon, colorectal, lung, ovarian cancer, lymphoma, and melanoma) [4], as well as tissues and organs from patients with chronic inflammatory disorders (rheumatoid arthritis, arteriosclerosis, inflammatory bowel disease, and complications from diabetes) [11]. In animal models, RAGE has been shown to accelerate the progression of many diseases such as sepsis and systemic bacterial infection, arthritis, multiple sclerosis, complications from diabetes, or cancer [13,14,15,16]

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