Lycopene Enhances the Sensitivity of Oral Squamous Cell Carcinoma to Cisplatin Through Inhibition of the PI3K/Akt Signaling Pathway and Reversal of Epithelial-Mesenchymal Transition

Ran Wang,1,2,* Xinxing Lu,3,* Riyue Yu,2 Zhaochen Shan1 1Outpatient Department of Oral and Maxillofacial Surgery, School of Stomatology, Capital Medical University, Beijing, People’s Republic of China; 2Department of Stomatology, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Gastrointestinal Cancer Center, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhaochen Shan, Outpatient Department of Oral and Maxillofacial Surgery, School of Stomatology, Capital Medical University, Beijing, 100071, People’s Republic of China, Email [email protected]: Cisplatin-based chemotherapy for oral squamous cell carcinoma (OSCC) is limited by intrinsic inefficacy and toxicity. Lycopene, a natural carotenoid, may enhance cisplatin’s therapeutic potential.Objective: To explore lycopene’s chemo-sensitizing effects on cisplatin and its mechanisms in OSCC.Methods: In vitro, CAL-27/SCC-9 cells were treated with lycopene and/or cisplatin; cell viability, colony formation, migration, invasion, and apoptosis were detected, and protein expression of MRP-1, PI3K/Akt/mTOR pathway components, and EMT markers was analyzed by Western blot. In vivo, a nude mouse xenograft model was used to verify the combination’s effect on tumor growth.Results: Compared with cisplatin alone, the lycopene-cisplatin combination significantly inhibited OSCC cell proliferation, colony formation, migration, and invasion, while promoting apoptosis. Mechanistically, lycopene reversed cisplatin-induced upregulation of MRP-1 and activation of the PI3K/Akt/mTOR pathway, and restored cisplatin-suppressed E-cadherin while reducing N-cadherin and EpCAM. In vivo, the combination reduced tumor growth vs cisplatin alone without increasing toxicity.Conclusion: This is the first report that lycopene enhances cisplatin sensitivity in OSCC by coupling inhibition of MRP-1-mediated drug efflux with suppression of PI3K/Akt/mTOR and EMT/stemness—filling the gap of lycopene’s synergistic mechanism with cisplatin, offering a strategy to improve therapeutic efficacy without exacerbating toxicity.Keywords: oral squamous cell carcinoma, lycopene, cisplatin, chemoresistance, PI3K/Akt pathway