Pusan National University Identifies Structure of Protein Complex Involved in Cancer Cells... Proposes Therapeutic Strategy

Development of a Next-Generation Targeted Anticancer Drug Candidate Without Toxicity
Confirmed Inhibition of Various Cancer Cell Proliferation, Including Lung, Colon, and Pancreatic Cancer, Without Toxicity to Normal Cells

A research team at Pusan National University has identified the structure of a protein complex involved in cancer cell survival and developed a peptide that inhibits this complex, demonstrating its cancer-suppressing effects.

A peptide is a molecule composed of two or more amino acids, which are the building blocks of proteins, and plays various roles in living organisms, including as hormones, enzymes, and signaling molecules.

Pusan National University (President Choi Jaewon) announced on May 9 that a research team led by Professor Jang Sebok from the Department of Molecular Biology has, for the first time in the world, analyzed at the atomic level the binding structure of the HMGB1 (High Mobility Group Box 1)-RAGE (Receptor for Advanced Glycation End-products) protein complex, which promotes the survival of cancer cells, using cryo-electron microscopy (Cryo-EM). Based on this structure, the team designed a peptide with the ability to inhibit cancer cell proliferation and migration, suggesting its potential as a next-generation anticancer drug candidate.

Professor Jang Sebok (left), Senior Researcher Kim Hyunjin. Provided by Pusan National University

Through Cryo-EM, the research team identified the binding site of the HMGB1-RAGE complex and confirmed the presence of electrostatic interactions between HMGB1 and RAGE. The newly developed peptide inhibits the formation of the HMGB1-RAGE complex by competitively binding to RAGE, a receptor for advanced glycation end-products. This peptide also suppresses the ERK1/2 (Extracellular signal-regulated kinase)-Drp1 (Dynamin-related protein 1) signaling pathway activated in cancer cells, significantly blocking autophagy, cell proliferation, and migration.

In particular, the study observed that administration of the peptide to lung, colon, and pancreatic cancer cell lines resulted in a significant decrease in ATP (adenosine triphosphate) production and inhibited cell migration in cancer cells. Furthermore, no toxicity was observed in normal cells, earning positive evaluations for safety.

Animal experiments also demonstrated high efficacy. In a lung cancer model implanted in immunodeficient mice, administration of the peptide alone reduced tumor volume and weight by more than 40%, with no observed toxicity. No cytotoxicity was found in normal cells, indicating promising results in terms of safety.

Existing RAGE inhibitors have had limitations due to high side effects and low selectivity caused by nonspecific binding. However, the peptide developed in this study precisely inhibits only the binding site of the complex, enabling a more targeted and specific mechanism of action. This greatly expands the therapeutic potential of the treatment.

Professor Jang Sebok explained, "Existing RAGE inhibitors have had clinical limitations due to low specificity and toxicity. The peptide-based therapy proposed in this study selectively blocks the activity of protein complexes involved in cancer cells by targeting specific protein-protein interactions, thereby maximizing anticancer effects while minimizing side effects."

The results of this study were published online on April 29 in 'Biomedicine & Pharmacotherapy,' a leading international journal in the biomedical field.

This research was supported by the Ministry of Science and ICT, the Ministry of Education, the National Research Foundation of Korea's Basic Research Program, and the Individual Basic Research Support Program. Professor Jang Sebok from the Department of Molecular Biology at Pusan National University served as the corresponding author, Jung Misook, CEO of Geumjeong Pharmaceutical, was the co-corresponding author, and Kim Hyunjin, Senior Researcher at the Pusan National University Life Systems Research Institute, participated as the first author. The results of this study have been registered as a domestic patent.