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S100P-derived RAGE antagonistic peptide reduces tumor growth and metastasis
Thiruvengadam Arumugam1, Vijaya Ramachandran, Sobeyda B Gomez
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Purpose:
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.
Experimental Design:
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.
Results:
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.
Conclusion:
RAP shows promise as a tool for the investigation of RAGE function and as an in vivo treatment for RAGE-related disorders.
Insights
A novel RAGE antagonist peptide (RAP) effectively blocks receptor for advanced glycation end products (RAGE) activation by multiple ligands. This peptide shows promise for treating RAGE-related disorders and investigating RAGE function.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- The receptor for advanced glycation end products (RAGE) is implicated in various pathologies, including cancer, diabetes, and neurodegenerative diseases.
- Currently, no RAGE inhibitors are widely used in clinical practice, highlighting a significant unmet medical need.
- RAGE signaling pathways are crucial in disease progression, making it a potential therapeutic target.
Purpose of the Study:
- To develop and characterize a novel small peptide antagonist for RAGE (RAP) capable of blocking its activation by multiple ligands.
- To evaluate the therapeutic potential of RAP in preclinical models of cancer, specifically pancreatic ductal adenocarcinoma (PDAC) and glioma.
Main Methods:
- Immunohistochemical analysis of human pancreatic tissues to visualize RAGE and its ligands (S100P, S100A4, HMGB-1).
- Silencing RAGE and its ligands using siRNA to assess functional roles in cancer cell behavior.
- ELISA to quantify interactions between RAGE and its ligands; peptide-based inhibition assays and NFκB reporter activity assays to evaluate RAP efficacy in blocking RAGE signaling.
Main Results:
- RAGE and its ligands were confirmed in human PDAC tissues; siRNA silencing reduced PDAC cell growth and migration.
- The developed RAP effectively inhibited interactions between RAGE and its ligands (S100P, S100A4, HMGB-1) at micromolar concentrations.
- RAP administration reduced RAGE-mediated NFκB activation in cancer cells and significantly inhibited tumor growth and metastasis in vivo models of pancreatic cancer and glioma.
Conclusions:
- The novel RAGE antagonist peptide (RAP) demonstrates potent inhibition of RAGE ligand interactions and downstream signaling.
- RAP effectively reduces tumor growth and metastasis in preclinical models, indicating its therapeutic potential.
- RAP serves as a valuable tool for studying RAGE function and offers a promising therapeutic strategy for RAGE-related diseases.
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