Inhibition of the Receptor for Advanced Glycation End Products Enhances the Cytotoxic Effect of Gemcitabine in Murine Pancreatic Tumors

Abstract

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.

S100s and HMGB1 Crosstalk in Pancreatic Cancer Tumors

“…In the nucleus, HMGB1 regulates gene transcription by binding to and stabilizing DNA, and has a tumor suppressor effect [ 4 ]. When present in the cytoplasm, HMGB1 increases drug resistance by promoting autophagy [ 4 , 60 , 61 ]. Finally, HMGB1 can also act as an alarmin or damage-associated molecular pattern (DAMP) by interacting with RAGE or Toll-like receptors (TLR) when secreted into the tumor microenvironment [ 5 , 62 , 63 ].…”

HMGB1/RAGE axis in tumor development: unraveling its significance

“…In human pancreatic cancer cells and tumors, it has been demonstrated that both RAGE ligands, HMGB1 and S100P, stimulate RAGE. However, the animal model used by the authors does not express functional S100P, suggesting that HMGB1 activation of RAGE can stimulate pancreatic cancer cells and promote their proliferation ( 91 ). Lan et al.…”

“…In a mouse model of pancreatic cancer treated with gemcitabine, inhibition of RAGE enhances gemcitabine-induced cell apoptosis. Hence, RAGE is believed to play a role in inhibiting cell apoptosis in pancreatic cancer ( 91 ). Silencing RAGE in prostate tumor cells results in decreased HMGB1 expression and increased expression of death receptors DR4 and DR5, demonstrating that disruption of the HMGB1-RAGE axis induces apoptosis in prostate tumors ( 102 ).…”

“…suggested that HMGB1 promotes EMT in prostate cancer PC3 cells by activating the RAGE/NF-κB signaling pathway, upregulating the expression of EMT markers MMP-1, MMP-3, and MMP-10, and promoting prostate cancer metastasis ( 116 ). Studies have shown that HMGB1 activates RAGE to affect the NF-κB signaling pathway by reducing p65 phosphorylation levels, promoting pancreatic cancer metastasis, and inducing chemoresistance to gemcitabine ( 91 ).…”

Receptor of advanced glycation end-products axis and gallbladder cancer: A forgotten connection that we should reconsider

“…The use of novel RAGE-targeting antibodies and blocking peptides derived from RAGE ligands such as S100P and HMGB1 has demonstrated to block the ability of ligands to stimulate RAGE activation in cancer cells both in vitro and in vivo models, thus inhibiting tumor growth, metastasis, and inflammation[ 69 ], as well as significant reductions in tumor growth with acceptable toxicity levels in several in vivo mouse adenocarcinoma models[ 70 , 71 ]. Furthermore, the treatment of cancer cell lines with anti-RAGE antibodies demonstrates that RAGE blocking may even enhance the chemotherapeutic effects of antineoplastic drugs[ 72 , 73 ].…”