Therapeutic Targeting of S100A2 Enhances Chemotherapy Efficacy in vitro in Oral Cancer

OBJECTIVE: Despite advancements in multimodal therapies, oral squamous cell carcinoma (OSCC) continues to exhibit poor clinical outcomes, particularly in advanced and recurrent cases. Recent studies have identified the calcium-binding protein S100A2 as a critical mediator of OSCC progression and resistance to therapy. Our prior work demonstrated that cytoplasmic overexpression of S100A2 in oral cancer patients is associated with tumor recurrence and reduced survival. Given its reported role in promoting epithelial-to-mesenchymal transition (EMT), cellular proliferation, and invasiveness, we investigated the in vitro functional impact of S100A2 inhibition in OSCC. METHODS: Silencing S100A2 significantly impaired tumor cell proliferation and enhanced apoptotic cell death, as evidenced by Annexin V and caspase-3 activation. RESULTS: Notably, S100A2-deficient OSCC cells exhibited increased sensitivity to chemotherapeutic agents, including carboplatin, 5-fluorouracil, paclitaxel, and doxorubicin, through mitochondrial apoptotic pathways. CONCLUSION: These findings position S100A2 as a potential therapeutic target for overcoming drug resistance and improving treatment efficacy in OSCC. Further mechanistic studies and in vivo validation are warranted to explore its translational relevance in clinical oncology.