Interplay of p62-mTORC1 and EGFR signaling promotes cisplatin resistance in oral cancer
Hsiu-Chuan Chang,
Cheng-Chieh Yang,
Lai-Keng Loi,
Chi-Hsun Hung,
Cheng-Hsien Wu,
Yu-Cheng Lin
Affiliations
Hsiu-Chuan Chang
Institute of Oral Biology, School of Dentistry, National Yang Ming Chiao Tung University, Taipei, Taiwan
Cheng-Chieh Yang
Department of Dentistry, School of Dentistry, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Stomatology, Oral & Maxillofacial Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
Lai-Keng Loi
Department of Dentistry, School of Dentistry, National Yang Ming Chiao Tung University, Taipei, Taiwan
Chi-Hsun Hung
Department of Stomatology, Oral & Maxillofacial Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
Cheng-Hsien Wu
Department of Stomatology, Oral & Maxillofacial Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
Yu-Cheng Lin
Department of Dentistry, School of Dentistry, National Yang Ming Chiao Tung University, Taipei, Taiwan; Oral Medicine Innovation Center (OMIC), National Yang Ming Chiao Tung University, Taipei, Taiwan; Corresponding author. Department of Dentistry, College of Dentistry National Yang Ming Chiao Tung University No. 155, Li-Nong St., Section 2, Taipei, Taiwan, 112.
Cisplatin resistance poses a major challenge in the treatment of oral squamous cell carcinoma (OSCC). Deeper investigations into the mechanisms underlying this drug resistance is of great importance. Here, we used cellular assays and clinical immunohistochemistry to examine molecular pathways involved in both innate and acquired cisplatin resistance. We demonstrated that the p62-mTORC1 signaling complex plays a pivotal role, and is driven by the EGFR signaling network, specifically through the PI3K-Akt axis and the transcription factor C/EBP-β. Elevated p-mTOR expression was associated with cancer relapse and poor prognosis among oral cancer patients. Additionally, we illustrated that mTOR inhibitors enhance the cytotoxic effect of cisplatin, by employing cancer stem cell characteristics. Our work unveils fundamental mechanisms for cisplatin resistance, thereby presenting therapeutic implications for OSCC.
