A1 Refereed original research article in a scientific journal
The Notch inhibitor, FLI-06, increases the chemosensitivity of head and neck Squamous cell carcinoma cells to taxanes-based treatment
Authors: Czerwonka, Arkadiusz; Kałafut, Joanna; Wang, Shaoxia; Anameric, Alinda; Przybyszewska-Podstawka, Alicja; Toriseva, Mervi; Nees, Matthias
Publisher: Elsevier
Publication year: 2024
Journal: Biomedicine and Pharmacotherapy
Journal name in source: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Journal acronym: Biomed Pharmacother
Article number: 116822
Volume: 177
ISSN: 0753-3322
eISSN: 1950-6007
DOI: https://doi.org/10.1016/j.biopha.2024.116822(external)
Web address : https://doi.org/10.1016/j.biopha.2024.116822(external)
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/456967690(external)
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 G1-phase and induction of apoptosis in HNSCC, which is accompanied by increased c-JunS63 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-JunS243 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.
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Funding information in the publication:
This research was funded by the Polish National Science Centre (NCN): UMO-2020/37/B/NZ4/03920, DEC-2021/41/B/NZ7/03786, and DEC-2021/41/N/NZ5/01938 and Polish National Agency for Academic Exchange (NAWA): PPI/APM/2019/1/00089/U/00001, Internal project “Grant innowacyjny G7” of Medical University of Lublin, and Jane & Aatos Erkko Foundation, project “Matrix Matters”.