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.
Pancreatic ductal adenocarcinoma (PDAC) remains a very difficult cancer to treat. Recent in vitro and in vivo studies suggest that the activation of the receptor for advanced glycation end products (RAGE) by its ligands stimulates pancreatic cancer cell proliferation and tumor growth. Additional studies show that, in the RAGE ligand, the high mobility group box 1 (HMGB1) protein plays an important role in chemoresistance against the cytotoxic agent gemcitabine by promoting cell survival through increased autophagy. We hypothesized that blocking the RAGE/HMGB1 interaction would enhance the cytotoxic effect of gemcitabine by reducing cell survival and autophagy. Using a preclinical mouse model of PDAC and a monoclonal antibody (IgG 2A11) as a RAGE inhibitor, we demonstrate that RAGE inhibition concurrent with gemcitabine treatment enhanced the cytotoxic effect of gemcitabine. The combination of IgG 2A11 and gemcitabine resulted in decreased autophagy compared to treatment with gemcitabine combined with control antibodies. Notably, we also observed that RAGE inhibition protected against excessive weight loss during treatment with gemcitabine. Our data suggest that the combination of gemcitabine with a RAGE inhibitor could be a promising therapeutic approach for the treatment of pancreatic cancer and needs to be further investigated.
Pancreatic cancer is currently the fourth leading cause of cancer deaths in the US with a dismal 5‐year survival rate of 7%. Despite several advancements in therapy, gemcitabine remains the standard treatment for pancreatic cancer. However, the modest survival advantage presented by gemcitabine evokes the need for a targeted therapeutic approach in addition to conventional treatment. The Receptor for advanced glycation end‐products (RAGE) is a cell surface receptor which has been demonstrated to be involved in pancreatic cancer progression. RAGE is also reported to facilitate pancreatic tumor cell survival by supporting autophagy and restricting apoptosis. Recent reports have illustrated RAGE as a potential mediator of chemo‐resistance in pancreatic cancer. HMGB1, one of the important ligands of RAGE, is released from necrotic cells upon treatment with gemcitabine. This HMGB1 triggers upregulation of RAGE in the tumor, making it resistant to chemotherapy. We intend to target pancreatic cancer with RAGE inhibitors in combination with gemcitabine to improve survival. We hypothesize that RAGE inhibitors can prevent the interaction between RAGE and its ligands, consequently sensitizing pancreatic cancer for gemcitabine.To accomplish the aim of our study we employed orthotopic mouse model of pancreatic cancer. KPC cells, derived from mice tumors, were implanted in the pancreas of C57BL/6 mice. The mice were divided into four treatment groups: (i) Saline control (ii) Gemcitabine (iii) RAGE inhibitor (anti‐RAGE antibody, IgG2A11) (iv) RAGE inhibitor + gemcitabine. At the end of the study, the tumors obtained from the different treatment groups were assessed for their size, weight and volume. Additionally, the tumors from the four treatment groups were analyzed for the expression of markers of cell proliferation (Ki67), autophagy (LC3), apoptosis (cleaved caspase 3) and cell survival (BCl2) by western blot and immunohistochemistry. We also compared the phosphorylation of ERK1/2 in the tumors from the four treatment groups by western blot.The data showed a statistically significant reduction in tumor weight in mice treated with the combination of anti‐RAGE antibody, IgG2A11 and gemcitabine as compared to the control group. We could also observe a significant decrease in the expression of LC3 and an increase in cleaved caspase 3 in the tumors treated with the combination as compared to the control group. There was also a significant reduction in the phosphorylation of ERK1/2 in tumors treated with anti‐RAGE antibody IgG2A11 and gemcitabine. These results imply that the combination of RAGE inhibitors and gemcitabine can be used as an approach to mitigate chemo‐resistance in pancreatic cancer.Support or Funding InformationCollege of Health Professions at NDSUNIH Grant Number P20 GM109024 from the National Institute of General Medicine (NIGMS)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Recent studies suggest that the Receptor for Advanced Glycation End Products (RAGE) and its ligands (S100P or HMGB1) are important contributors to the progression of pancreatic cancer. Being a cell surface receptor, RAGE possesses a large extracellular domain that binds its activating ligands. We reasoned that monoclonal antibodies that block the interaction between RAGE and its ligands could impact the progression of pancreatic cancer. We have generated a panel of antibodies recognizing different domains of the receptor and are currently testing their inhibitory effects, in pancreatic cancer cells and in small animal models. Citation Format: Priyanka Swami, Venkata Indurthi, Stefan W. Vetter, Estelle Leclerc.{Authors}. Targeting RAGE in pancreatic cancer using monoclonal antibodies. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A37.
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