Metformin radiosensitizes OSCC in 2D and 3D models: possible involvement of CAF-1.

Objective: This study investigated metformin as a sensitizer for radiotherapy in oral squamous cell carcinoma (OSCC) to reduce the radiation intensity. It evaluated the drug's effect on Chromatin Assembly Factor-1 (CAF-1) expression, whose high levels correlate with worse prognosis of this cancer.

Methods: The effects of metformin, alone and with radiotherapy, were evaluated on CAL27 (HPV-) and SCC154 (HPV+) OSCC cells. The analyses were performed on cell monolayers by colony-forming assay, motility, and confocal microscopy. In spheroid 3D models, the sensitizing effect of metformin was assessed by measuring areas. CAF-1 expression affected by metformin was evaluated via Western blot, and its role was investigated by siRNAs.

Results: Metformin reduced the cells' ability to form colonies, migrate and invade, and promoted the acquisition of a less aggressive phenotype by increased E-cadherin and decreased N-cadherin expressions. Moreover, metformin lowered the IC50 of radiotherapy and showed strong effects on spheroid growth. Metformin downmodulated the expression of the major subunits of CAF-1, and the knockdown of this protein by siRNAs elicited a metformin-like effect on cell aggressiveness.

Conclusions: Metformin emerged as a promising adjuvant drug in OSCC because of its effects on cell aggressiveness and radiosensitizing action. These activities could be CAF-1-mediated.