Activity of novel short pigment epithelium-derived factor-derived peptides in head and neck squamous cell carcinoma: effects on cell viability, metabolism, irradiation sensitivity, and mitochondrial function.

OBJECTIVES: Pigment epithelium-derived factor (PEDF) has anti-tumour properties mediated through distinct functional peptide domains. In this study, we investigated the biological effects of PEDF-derived peptides (coded S, V, and 44-mer) in head and neck squamous cell carcinoma (HNSCC), focussing on cell viability, migration, spheroid growth, metabolism, mitochondrial function, and response to irradiation. METHODS: Cal-27 (oral squamous cell carcinoma, OSCC) and FaDu (oropharyngeal squamous cell carcinoma, OPSCC) cells treated with the 12-, 13-, and 44-mer peptides were assessed using 2D and 3D culture models, metabolic assays, JC-10 mitochondrial membrane potential analysis, and biomarker analysis. KEY FINDINGS: PEDF-derived peptides reduced cell viability in a dose- and time-dependent manner in both cells. Irradiation further enhanced cytotoxicity compared to irradiation alone, suggesting a potential radiosensitizing effect. Migration was not affected, while there was a peptide-specific spheroid growth reduction in Cal-27 cells, particularly for peptide V. There was increased glucose uptake and GLUT4 expression were observed in FaDu cells, but not in Cal-27 cells. JC-10 analysis demonstrated a significant reduction in mitochondrial membrane potential in Cal-27 cells, indicating mitochondrial dysfunction, while FaDu cells exhibited less changes. CONCLUSIONS: These findings suggest that these novel PEDF-derived peptides may represent promising therapeutic candidates for HNSCC, particularly in combination with radiotherapy.