Isoorientin inhibits epithelial-to-mesenchymal properties and cancer stem-cell-like features in oral squamous cell carcinoma by blocking Wnt/β-catenin/STAT3 axis

Shao Cheng Liu, Chin Sheng Huang, Chih Ming Huang, Ming Shou Hsieh, Mao Suan Huang, Iat Hang Fong, Chi Tai Yeh, Chih Cheng Lin

Research output: Contribution to journalArticlepeer-review

Abstract

Oral squamous cell carcinoma (OSCC) is among the most prevalent cancers of the head and neck. This study revealed that isoorientin attenuates OSCC cell stemness and epithelial–mesenchymal transition potential through the inhibition of JAK/signal transducer and activator of transcription 3 (STAT3) and Wnt/β-catenin signaling in cell lines. Our findings indicated that isoorientin is a potential inhibitor of β-catenin/STAT3 in vitro and in vivo. We analyzed possible synergism between isoorientin and cisplatin in OSCC. A sulforhodamine B assay, colony formation assay, tumorsphere-formation assay, and Wnt reporter activity assay were used for determining cell invasion, cell migration, drug cytotoxicity, and cell viability with potential molecular mechanisms in vitro. Isoorientin reduced the expression of p-STAT3, β-catenin, and p-GSK3 as well as downstream effectors TCF1/TCF7 and LEF1 and significantly reduced β-catenin colocalization in the nucleus. Isoorientin markedly strengthened the cytotoxic effects of cisplatin against SAS and SCC-25. Therefore, combining isoorientin and cisplatin treatments can potentially improve the anticancer effect of cisplatin. Isoorientin inhibited the tumorigenicity and growth of OSCC through the abrogation of Wnt/β-catenin/STAT3 signaling in vivo. Thus, isoorientin disrupted the β-catenin signaling pathway through the inactivation of STAT3 signaling. In conclusion, targeting OSCC-SC–mediated stemness with isoorientin to eradicate OSCC-SCs may be an effective strategy for preventing relapse and metastasis of OSCC and providing long-term survival benefits.

Original languageEnglish
Article number115581
JournalToxicology and Applied Pharmacology
Volume424
DOIs
Publication statusPublished - Aug 2021

Keywords

  • Isoorientin
  • Oral squamous cell carcinoma
  • STAT3/Wnt/β-catenin pathway

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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