2. Academic Validation
  3. Metformin overcomes chemoresistance by regulating stemness via KLF4 in oral squamous cell carcinoma

Metformin overcomes chemoresistance by regulating stemness via KLF4 in oral squamous cell carcinoma

  • Oral Dis. 2024 Jul 22. doi: 10.1111/odi.15075.
Tong Zhou 1,  Xuefeng Zhang 1,  Dan Yang 1,  Weideng Wei 1,  Jianguo Gan 1,  Xiaoqiang Xia 1,  Qianming Chen 2,  Jian Jiang 3,  Xiaodong Feng 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Frontier Innovation Center for Dental Medicine Plus & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
  • 2 Key Laboratory of Oral Biomedical Research of Zhejiang Province, Affiliated Stomatology Hospital, Zhejiang University School of Stomatology, Hangzhou, Zhejiang, China.
  • 3 Department of Head and Neck Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
PMID: 39039738 DOI: 10.1111/odi.15075
Abstract

Objective: Chemoresistance is a common event after chemotherapy, including oral squamous cell carcinoma (OSCC). Accumulated evidence suggests that the Cancer stemness significantly contributes to therapy resistance. An unresolved question remains regarding how to effectively overcome OSCC chemoresistance by targeting stemness. This study aims to investigate the antitumor effect of metformin and clarify the potential molecular mechanisms.

Methods: Cellular models resistant to chemotherapy were established, and their viability and sphere-forming ability were assessed using CCK-8 and soft agar formation assays, respectively. RNA-seq and Western blotting analyses were employed to delve into the molecular pathways. Furthermore, to corroborate the inhibitory effects of metformin and cisplatin at an animal level, a subcutaneous tumor transplantation model was instituted.

Results: Metformin as a monotherapy exhibited inhibition of stemness traits via Krüppel-like factor 4 (KLF4). Metformin and cisplatin can synergically inhibit cell proliferation and induce cell Apoptosis. Animal experiments confirmed the inhibitory effect of cisplatin and metformin on tumor in mice.

Conclusion: Our study proposes a potential therapeutic approach of combining chemotherapy with metformin to overcome chemoresistance in OSCC.

Keywords

KLF4; cancer stemness; chemoresistance; metformin; oral squamous cell carcinoma.

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