Imipramine blue halts head and neck cancer invasion through promoting F-box and leucine-rich repeat protein 14-mediated Twist1 degradation

W. H. Yang, Y. H. Su, W. H. Hsu, C. C. Wang, J. L. Arbiser, M. H. Yang

研究成果: 雜誌貢獻文章同行評審

25 引文 斯高帕斯(Scopus)

摘要

The unique characteristic of head and neck squamous cell carcinoma (HNSCC) is that local invasion rather than distant metastasis is the major route for dissemination. Therefore, targeting the locally invasive cancer cells is more important than preventing systemic metastasis in HNSCC and other invasive-predominant cancers. We previously demonstrate a specific mechanism for HNSCC local invasion: the epithelial-mesenchymal transition (EMT) regulator Twist1 represses microRNA let-7i expression, leading to the activation of the small GTPase Rac1 and engendering the mesenchymal-mode movement in three-dimensional (3D) culture. However, targeting the EMT regulator is relatively difficult because of its transcription factor nature and the strategy for confining HNSCC invasion to facilitate local treatment is limited. Imipramine blue (IB) is a newly identified anti-invasive compound that effectively inhibits glioma invasion. Here we demonstrate that in HNSCC cells, a noncytotoxic dose of IB represses mesenchymal-mode migration in two-and-a-half-dimensional/3D culture system. IB suppresses EMT and stemness of HNSCC cells through inhibition of Twist1-mediated let-7i downregulation and Rac1 activation and the EMT signalling. Mechanistically, IB inhibits reactive oxygen species-induced nuclear factor-κB pathway activation. Importantly, IB promotes degradation of the EMT inducer Twist1 by enhancing F-box and leucine-rich repeat protein 14 (FBXL14)-mediated polyubiquitination of Twist1. Together, this study demonstrates the potent anti-invasion and EMT-inhibition effect of IB, suggesting the potential of IB in treating local invasion-predominant cancers.
原文英語
頁(從 - 到)2287-2298
頁數12
期刊Oncogene
35
發行號18
DOIs
出版狀態已發佈 - 五月 5 2016
對外發佈Yes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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