S100P-Derived RAGE Antagonistic Peptide Reduces Tumor Growth and Metastasis

• Published in: Clinical cancer research 2012-08, Vol.18 (16), p.4356-4364
• Main Authors: ARUMUGAM, Thiruvengadam, RAMACHANDRAN, Vijaya, GOMEZ, Sobeyda B, SCHMIDT, Ann M, LOGSDON, Craig D
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Calcium-Binding Proteins - chemistry; Cell Line, Tumor; Cell Proliferation - drug effects; HMGB1 Protein - metabolism; Humans; Ligands; Male; Medical sciences; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Proteins - chemistry; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; NF-kappa B - metabolism; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Peptides - administration & dosage; Peptides - pharmacology; Pharmacology. Drug treatments; Protein Binding - drug effects; Receptor for Advanced Glycation End Products; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - metabolism; S100 Calcium-Binding Protein A4; S100 Proteins - chemistry; S100 Proteins - metabolism; S100 Proteins - pharmacology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-12-0221

The receptor for advanced glycation end products (RAGE) contributes to multiple pathologies, including diabetes, arthritis, neurodegenerative diseases, and cancer. Despite the obvious need, no RAGE inhibitors are in common clinical use. Therefore, we developed a novel small RAGE antagonist peptide (RAP) that blocks activation by multiple ligands. RAGE and its ligands were visualized by immunohistochemical analysis of human pancreatic tissues, and siRNA was used to analyze their functions. Interactions between RAGE and S100P, S100A4, and HMGB-1 were measured by ELISA. Three S100P-derived small antagonistic peptides were designed, synthesized, and tested for inhibition of RAGE binding. The effects of the peptide blockers on NFκB-luciferase reporter activity was used to assess effects on RAGE-mediated signaling. The most effective peptide was tested on glioma and pancreatic ductal adenocarcinoma (PDAC) models. Immunohistochemical analysis confirmed the expression of RAGE and its ligands S100P, S100A4, and HMGB-1 in human PDAC. siRNA silencing of RAGE or its ligands reduced the growth and migration of PDAC cells in vitro. The most effective RAP inhibited the interaction of S100P, S100A4, and HMGB-1 with RAGE at micromolar concentrations. RAP also reduced the ability of the ligands to stimulate RAGE activation of NFκB in cancer cells in vitro and in vivo. Importantly, systemic in vivo administration of RAP reduced the growth and metastasis of pancreatic tumors and also inhibited glioma tumor growth. RAP shows promise as a tool for the investigation of RAGE function and as an in vivo treatment for RAGE-related disorders.