Oleanolic acid inhibits aldo-keto reductase family 1 member B10-induced cancer stemness and avoids cisplatin-based chemotherapy resistance via the Snail signaling pathway in oral squamous cell carcinoma cell lines

  • J Dent Sci. 2025 Jan;20(1):100-108. doi: 10.1016/j.jds.2024.09.018.
Hui-Hsin Ko  1  2  3 ,  Han-Yi E Chou  4  2  5 ,  Hsin-Han Hou  4  2  5 ,  Wei-Ting Kuo  4  2  5 ,  Wei-Wen Liu  4  2  5 ,  Mark Yen-Ping Kuo  1  4  2 ,  Shih-Jung Cheng  1  4  2  5
Affiliations
  • 1. Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.
  • 2. Department of Dentistry, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan.
  • 3. Department of Dentistry, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan.
  • 4. School of Dentistry, National Taiwan University, Taipei, Taiwan.
  • 5. Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan.
PMID: 39873100 DOI: 10.1016/j.jds.2024.09.018
Abstract

Background/purpose: Oral squamous cell carcinoma (OSCC) is a common malignancy often associated with poor prognosis due to chemoresistance. In this study, we investigated whether arecoline, a major alkaloid in betel nuts, can stimulate aldo-keto reductase family 1 member B10 (AKR1B10) levels in OSCC, promoting Cancer stemness and leading to resistance to cisplatin (CDDP)-based chemotherapy.

Materials and methods: Gain- and Loss- of AKR1B10 functions were analyzed using WB and q-PCR of OSCC cells. Stemness, epithelial mesenchymal transition (EMT) markers, and CDDP drug resistance in overexpressed AKR1B10 were also identified.

Results: Upregulated AKR1B10 in OSCC significantly increased cell motility and aggregation. The results also showed that the canonical TGF-β1-Smad3 pathway was involved in arecoline-induced AKR1B10 expression, further increasing Cancer stemness with CDDP resistance via the Snail-dependent EMT pathway. Moreover, oleanolic acid (OA) and ROS/RNS (reactive oxygen/nitrogen species) inhibitors effectively reversed AKR1B10-induced CDDP-resistance.

Conclusion: Arecoline-induced ROS/RNS to hyper-activate AKR1B10 in tumor sphere cells via the TGF-β1-Smad3 pathway. Furthermore, AKR1B10 enhanced CDDP resistance in OSCC cells via EMT-inducing markers. Finally, Finally, OA may efficiently target CDDP resistance, reverse stemness in OSCC cells, and have the potential as a novel Anticancer drug.

Keywords
Aldo-keto reductase family 1 member B10 (AKR1B10); Oleanolic acid (OA); Oral cancer; Oral squamous cell carcinoma (OSCC); Stemness.
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