The Notch inhibitor, FLI-06, increases the chemosensitivity of head and neck Squamous cell carcinoma cells to taxanes-based treatment.

Autor: Czerwonka A; Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin 20-093, Poland. Electronic address: arkadiusz.czerwonka@umlub.pl., Kałafut J; Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin 20-093, Poland., Wang S; Institute of Biomedicine, Cancer Research Unit and FICAN West Cancer Centre Laboratory, University of Turku and Turku University Hospital, Turku, Finland., Anameric A; Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin 20-093, Poland., Przybyszewska-Podstawka A; Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin 20-093, Poland., Toriseva M; Institute of Biomedicine, Cancer Research Unit and FICAN West Cancer Centre Laboratory, University of Turku and Turku University Hospital, Turku, Finland., Nees M; Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin 20-093, Poland.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Aug; Vol. 177, pp. 116822. Date of Electronic Publication: 2024 Jun 20.
DOI: 10.1016/j.biopha.2024.116822
Abstrakt: Aberration of Notch signaling is one of the key events involved in the development and progression of head and neck squamous cell carcinoma (HNSCC). The Notch pathway controls the tissue-specific differentiation of normal squamous epithelial cells and is frequently altered in squamous carcinomas, thus affecting their proliferation, growth, survival, and chemosensitivity or resistance against anti-cancer agents. In this study, we show that the use of novel, small-molecule inhibitors of Notch signaling, such as FLI-06, can have a beneficial effect on increasing the chemosensitivity of HNSCC to taxane-based chemotherapy. Inhibition of Notch signaling by FLI-06 alone virtually blocks the proliferation and growth of HNSCC cells in both 2D and 3D cultures and the zebrafish model, which is accompanied by down-regulation of key Notch target genes and proteins. Mechanistically, FLI-06 treatment causes cell cycle arrest in the G 1 -phase and induction of apoptosis in HNSCC, which is accompanied by increased c-Jun S63 phosphorylation. Combining FLI-06 with Docetaxel shows a synergistic effect and partially blocks the cell growth of aggressive HNSCC cells via enhanced apoptosis and modification of c-Jun S243 phosphorylation via GSK-3β inhibition. In conclusion, inhibition of Notch signaling in HNSCC cells that retain active Notch signaling significantly supports taxane-based anticancer activities via modulation of both the GSK-3β and the c-Jun.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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