Evaluation of the anticancer activity of RIN-1, a Notch signaling modulator, in head and neck squamous cell carcinoma
Abstract Notch signalling is one of the key molecular pathways involved in cell-to-cell signal transduction. Although the mechanisms of action of the NOTCH receptors are already relatively well known, their biological implications remain unclear, especially during the initiation and progression of h...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-39472-0 |
| _version_ | 1797452600915787776 |
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| author | Arkadiusz Czerwonka Joanna Kałafut Shaoxia Wang Alinda Anameric Alicja Przybyszewska-Podstawka Jesse Mattsson Mahtab Karbasian Doriane Le Manach Mervi Toriseva Matthias Nees |
| author_facet | Arkadiusz Czerwonka Joanna Kałafut Shaoxia Wang Alinda Anameric Alicja Przybyszewska-Podstawka Jesse Mattsson Mahtab Karbasian Doriane Le Manach Mervi Toriseva Matthias Nees |
| author_sort | Arkadiusz Czerwonka |
| collection | DOAJ |
| description | Abstract Notch signalling is one of the key molecular pathways involved in cell-to-cell signal transduction. Although the mechanisms of action of the NOTCH receptors are already relatively well known, their biological implications remain unclear, especially during the initiation and progression of head and neck squamous cell carcinoma (HNSCC). Here, we present the growth- and differentiation-modulating effects of various “next generation” small molecule Notch modulators represented by RIN-1, and CB-103, on HNSCC, compared to gamma secretase inhibitors as “conventional” NOTCH interfering compounds, like DAPT. These molecules were tested in different cell- and tissue culture conditions represented by 2D monolayer, non-adherent or spheroid culture, 3D organoid cultures, and zebrafish in vivo model. The most pronounced, pleiotropic effects were observed for the NOTCH modulator RIN-1. At the molecular level, RIN-1-dependent activation of Notch signalling led to characteristic changes in the expression of NOTCH-regulated targets, i.e., the transcriptional suppressors HES1 and HEY1, p21 (CDKN1A) cell cycle inhibitor, and pro-apoptotic BAX markers. These changes led to restriction of proliferation, growth, and reduced motility of HNSCC cells in 2D cultures. Consequently, cell cycle arrest in the G2-M phase and induction of apoptosis were observed. Similar anticancer effects were observed in 3D cultures and in the zebrafish model. In contrast, RIN-1 treatment resulted in inhibition of Notch signalling and the growth of HNSCC spheroids under non-adherent cell culture conditions. Our results suggest that modulation of Notch signalling could be used as a chemotherapeutic agent in selected patients with intact NOTCH signaling. |
| first_indexed | 2024-03-09T15:10:59Z |
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| id | doaj.art-9c02c842501f4c619df5ba8b69591f58 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-09T15:10:59Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-9c02c842501f4c619df5ba8b69591f582023-11-26T13:22:43ZengNature PortfolioScientific Reports2045-23222023-08-0113111710.1038/s41598-023-39472-0Evaluation of the anticancer activity of RIN-1, a Notch signaling modulator, in head and neck squamous cell carcinomaArkadiusz Czerwonka0Joanna Kałafut1Shaoxia Wang2Alinda Anameric3Alicja Przybyszewska-Podstawka4Jesse Mattsson5Mahtab Karbasian6Doriane Le Manach7Mervi Toriseva8Matthias Nees9Department of Biochemistry and Molecular Biology, Medical University of LublinDepartment of Biochemistry and Molecular Biology, Medical University of LublinFICAN West Cancer Centre Laboratory, Cancer Research Unit, Institute of Biomedicine, Turku University Hospital, University of TurkuDepartment of Biochemistry and Molecular Biology, Medical University of LublinDepartment of Biochemistry and Molecular Biology, Medical University of LublinFICAN West Cancer Centre Laboratory, Cancer Research Unit, Institute of Biomedicine, Turku University Hospital, University of TurkuFICAN West Cancer Centre Laboratory, Cancer Research Unit, Institute of Biomedicine, Turku University Hospital, University of TurkuDepartment of Biochemistry and Molecular Biology, Medical University of LublinFICAN West Cancer Centre Laboratory, Cancer Research Unit, Institute of Biomedicine, Turku University Hospital, University of TurkuDepartment of Biochemistry and Molecular Biology, Medical University of LublinAbstract Notch signalling is one of the key molecular pathways involved in cell-to-cell signal transduction. Although the mechanisms of action of the NOTCH receptors are already relatively well known, their biological implications remain unclear, especially during the initiation and progression of head and neck squamous cell carcinoma (HNSCC). Here, we present the growth- and differentiation-modulating effects of various “next generation” small molecule Notch modulators represented by RIN-1, and CB-103, on HNSCC, compared to gamma secretase inhibitors as “conventional” NOTCH interfering compounds, like DAPT. These molecules were tested in different cell- and tissue culture conditions represented by 2D monolayer, non-adherent or spheroid culture, 3D organoid cultures, and zebrafish in vivo model. The most pronounced, pleiotropic effects were observed for the NOTCH modulator RIN-1. At the molecular level, RIN-1-dependent activation of Notch signalling led to characteristic changes in the expression of NOTCH-regulated targets, i.e., the transcriptional suppressors HES1 and HEY1, p21 (CDKN1A) cell cycle inhibitor, and pro-apoptotic BAX markers. These changes led to restriction of proliferation, growth, and reduced motility of HNSCC cells in 2D cultures. Consequently, cell cycle arrest in the G2-M phase and induction of apoptosis were observed. Similar anticancer effects were observed in 3D cultures and in the zebrafish model. In contrast, RIN-1 treatment resulted in inhibition of Notch signalling and the growth of HNSCC spheroids under non-adherent cell culture conditions. Our results suggest that modulation of Notch signalling could be used as a chemotherapeutic agent in selected patients with intact NOTCH signaling.https://doi.org/10.1038/s41598-023-39472-0 |
| spellingShingle | Arkadiusz Czerwonka Joanna Kałafut Shaoxia Wang Alinda Anameric Alicja Przybyszewska-Podstawka Jesse Mattsson Mahtab Karbasian Doriane Le Manach Mervi Toriseva Matthias Nees Evaluation of the anticancer activity of RIN-1, a Notch signaling modulator, in head and neck squamous cell carcinoma Scientific Reports |
| title | Evaluation of the anticancer activity of RIN-1, a Notch signaling modulator, in head and neck squamous cell carcinoma |
| title_full | Evaluation of the anticancer activity of RIN-1, a Notch signaling modulator, in head and neck squamous cell carcinoma |
| title_fullStr | Evaluation of the anticancer activity of RIN-1, a Notch signaling modulator, in head and neck squamous cell carcinoma |
| title_full_unstemmed | Evaluation of the anticancer activity of RIN-1, a Notch signaling modulator, in head and neck squamous cell carcinoma |
| title_short | Evaluation of the anticancer activity of RIN-1, a Notch signaling modulator, in head and neck squamous cell carcinoma |
| title_sort | evaluation of the anticancer activity of rin 1 a notch signaling modulator in head and neck squamous cell carcinoma |
| url | https://doi.org/10.1038/s41598-023-39472-0 |
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