Inhibiting NHEJ in HNSCC cell lines by the ligase IV inhibitor SCR130 has limited radiosensitizing effects
Abstract Radiotherapy (RT) is a relevant treatment for head and neck squamous cell carcinoma (HNSCC) patients but radioresistance, which depends on DNA damage response (DDR), restrains outcome. Therefore, manipulating DDR by small molecule inhibitors (SMI) is a promising treatment option. The main D...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-05-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-03159-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850269252069621760 |
|---|---|
| author | Laura S. Hildebrand Tina Jost Marion Schindler Anja Derer Gregor Fuhrmann Rainer Fietkau Luitpold V. Distel |
| author_facet | Laura S. Hildebrand Tina Jost Marion Schindler Anja Derer Gregor Fuhrmann Rainer Fietkau Luitpold V. Distel |
| author_sort | Laura S. Hildebrand |
| collection | DOAJ |
| description | Abstract Radiotherapy (RT) is a relevant treatment for head and neck squamous cell carcinoma (HNSCC) patients but radioresistance, which depends on DNA damage response (DDR), restrains outcome. Therefore, manipulating DDR by small molecule inhibitors (SMI) is a promising treatment option. The main DNA double strand break (DSB) repair mechanisms in healthy mammalian cells are homologous recombination (HR) and non-homologous end joining (NHEJ). It is known that HR is already often impaired in tumors because of cancerous transitions. Therefore, additionally inhibiting NHEJ is a possibility to specifically target tumor cells and spare healthy tissue, which has the alternative DSB repair mechanism available. We treated HNSCC and healthy fibroblast cell lines with 30 µM of the ligase IV inhibitor SCR130 and a single dose of 2 Gy (Gy) ionizing radiation (IR) to investigate the inhibitor’s radiosensitizing effect. In short, the effect of SCR130 in combination with IR on cell death, clonogenicity, and DNA damage is limited and highly cell line specific. Nevertheless, SCR130 increases the number of cells in G0/G1 phase concomitant with gained p21 expression consistently. We suggest that SCR130 in combination with IR has anti-proliferative effects, but an escape of the cells by upregulation of ligase IV resulting from the treatment is possible. |
| format | Article |
| id | doaj-art-ae76db41972f4dcca6a38d4b99bbb0f9 |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-ae76db41972f4dcca6a38d4b99bbb0f92025-08-20T01:53:11ZengNature PortfolioScientific Reports2045-23222025-05-0115111810.1038/s41598-025-03159-5Inhibiting NHEJ in HNSCC cell lines by the ligase IV inhibitor SCR130 has limited radiosensitizing effectsLaura S. Hildebrand0Tina Jost1Marion Schindler2Anja Derer3Gregor Fuhrmann4Rainer Fietkau5Luitpold V. Distel6Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN)Department of Biology, Pharmaceutical Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN)Department of Biology, Pharmaceutical Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)Abstract Radiotherapy (RT) is a relevant treatment for head and neck squamous cell carcinoma (HNSCC) patients but radioresistance, which depends on DNA damage response (DDR), restrains outcome. Therefore, manipulating DDR by small molecule inhibitors (SMI) is a promising treatment option. The main DNA double strand break (DSB) repair mechanisms in healthy mammalian cells are homologous recombination (HR) and non-homologous end joining (NHEJ). It is known that HR is already often impaired in tumors because of cancerous transitions. Therefore, additionally inhibiting NHEJ is a possibility to specifically target tumor cells and spare healthy tissue, which has the alternative DSB repair mechanism available. We treated HNSCC and healthy fibroblast cell lines with 30 µM of the ligase IV inhibitor SCR130 and a single dose of 2 Gy (Gy) ionizing radiation (IR) to investigate the inhibitor’s radiosensitizing effect. In short, the effect of SCR130 in combination with IR on cell death, clonogenicity, and DNA damage is limited and highly cell line specific. Nevertheless, SCR130 increases the number of cells in G0/G1 phase concomitant with gained p21 expression consistently. We suggest that SCR130 in combination with IR has anti-proliferative effects, but an escape of the cells by upregulation of ligase IV resulting from the treatment is possible.https://doi.org/10.1038/s41598-025-03159-5Ligase IVSCR130Head and neck squamous cell carcinomaDNA damage responseRadiation sensitivityIonizing radiation |
| spellingShingle | Laura S. Hildebrand Tina Jost Marion Schindler Anja Derer Gregor Fuhrmann Rainer Fietkau Luitpold V. Distel Inhibiting NHEJ in HNSCC cell lines by the ligase IV inhibitor SCR130 has limited radiosensitizing effects Scientific Reports Ligase IV SCR130 Head and neck squamous cell carcinoma DNA damage response Radiation sensitivity Ionizing radiation |
| title | Inhibiting NHEJ in HNSCC cell lines by the ligase IV inhibitor SCR130 has limited radiosensitizing effects |
| title_full | Inhibiting NHEJ in HNSCC cell lines by the ligase IV inhibitor SCR130 has limited radiosensitizing effects |
| title_fullStr | Inhibiting NHEJ in HNSCC cell lines by the ligase IV inhibitor SCR130 has limited radiosensitizing effects |
| title_full_unstemmed | Inhibiting NHEJ in HNSCC cell lines by the ligase IV inhibitor SCR130 has limited radiosensitizing effects |
| title_short | Inhibiting NHEJ in HNSCC cell lines by the ligase IV inhibitor SCR130 has limited radiosensitizing effects |
| title_sort | inhibiting nhej in hnscc cell lines by the ligase iv inhibitor scr130 has limited radiosensitizing effects |
| topic | Ligase IV SCR130 Head and neck squamous cell carcinoma DNA damage response Radiation sensitivity Ionizing radiation |
| url | https://doi.org/10.1038/s41598-025-03159-5 |
| work_keys_str_mv | AT laurashildebrand inhibitingnhejinhnscccelllinesbytheligaseivinhibitorscr130haslimitedradiosensitizingeffects AT tinajost inhibitingnhejinhnscccelllinesbytheligaseivinhibitorscr130haslimitedradiosensitizingeffects AT marionschindler inhibitingnhejinhnscccelllinesbytheligaseivinhibitorscr130haslimitedradiosensitizingeffects AT anjaderer inhibitingnhejinhnscccelllinesbytheligaseivinhibitorscr130haslimitedradiosensitizingeffects AT gregorfuhrmann inhibitingnhejinhnscccelllinesbytheligaseivinhibitorscr130haslimitedradiosensitizingeffects AT rainerfietkau inhibitingnhejinhnscccelllinesbytheligaseivinhibitorscr130haslimitedradiosensitizingeffects AT luitpoldvdistel inhibitingnhejinhnscccelllinesbytheligaseivinhibitorscr130haslimitedradiosensitizingeffects |