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

Oncogene volume 35, pages 2287–2298 (2016)Cite this article

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Abstract

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.

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Acknowledgements

We thank Professor Víctor M Díaz (Universitat Pompeu Fabra, Barcelona, Spain) for the generous gifts of pcDNA3-myc-FBXL14 and pcDNA3-FBXL14ΔF plasmids. We thank Professor Kuo-Wei Chang (National Yang-Ming University, Taiwan) for providing OECM-1 cell line. This work was supported by Ministry of Science and Technology (103-2321-B-010-019, 103-2314-B-010-034, 103-2633-H-010-001, and 103-2314-B-010-035 to M-HY), Taipei Veterans General Hospital (V104-E8-001 to M-HY), a grant from Ministry of Education, Aim for the Top University Plan (to M-HY) and a grant from the Ministry of Health and Welfare, Center of Excellence for Cancer Research (MOHW104-TDU-B-211-124-001 to M-HY).

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Authors and Affiliations

  1. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

    W-H Yang, Y-H Su, W-H Hsu & M-H Yang

  2. Department of Otolaryngology-Head & Neck Surgery, Taichung Veterans General Hospital, Taichung, Taiwan

    C-C Wang

  3. School of Medicine, National Yang-Ming University, Taipei, Taiwan

    C-C Wang

  4. School of Speech Language Pathology & Audiology, Chung-Shan Medical University, Taichung, Taiwan

    C-C Wang

  5. Department of Dermatology, Emory School of Medicine, Atlanta, GA, USA

    J L Arbiser

  6. Atlanta Veterans Administration Medical Center, Atlanta, GA, USA

    J L Arbiser

  7. Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei, Taiwan

    M-H Yang

  8. Genome Research Center, National Yang-Ming University, Taipei, Taiwan

    M-H Yang

  9. Division of Hematology-Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    M-H Yang

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  1. W-H Yang
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Correspondence to J L Arbiser or M-H Yang.

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Competing interests

Emory University holds the intellectual property to imipramine blue and that Jack L Arbiser is the inventor. Emory University has licensed the intellectual property to ABBY Therapeutics.

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Yang, WH., Su, YH., Hsu, WH. et al. Imipramine blue halts head and neck cancer invasion through promoting F-box and leucine-rich repeat protein 14-mediated Twist1 degradation. Oncogene 35, 2287–2298 (2016). https://doi.org/10.1038/onc.2015.291

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