Syntaxin 18 regulates the DNA damage response and epithelial-to-mesenchymal transition to promote radiation resistance of lung cancer
Abstract Radiotherapy is an important modality in lung cancer treatment. Despite advances in treatment planning and dose delivery, patient benefit is still limited by in-field relapse and metastatic recurrence. Simultaneous application of cisplatinum-based chemotherapy leads to moderately improved o...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-06-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-04978-4 |
| _version_ | 1811258041980420096 |
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| author | Clotilde Thumser-Henner Sebastian Oeck Sophie Kalmbach Jan Forster Franziska Kindl Ali Sak Alexander Schramm Martin Schuler |
| author_facet | Clotilde Thumser-Henner Sebastian Oeck Sophie Kalmbach Jan Forster Franziska Kindl Ali Sak Alexander Schramm Martin Schuler |
| author_sort | Clotilde Thumser-Henner |
| collection | DOAJ |
| description | Abstract Radiotherapy is an important modality in lung cancer treatment. Despite advances in treatment planning and dose delivery, patient benefit is still limited by in-field relapse and metastatic recurrence. Simultaneous application of cisplatinum-based chemotherapy leads to moderately improved outcomes, thus providing proof-of-concept for radiosensitization strategies in lung cancer. In an unbiased functional genetic screen for radiosensitization targets in lung cancer, we identified syntaxin 18, a protein involved in retrograde vesicular transport between the Golgi apparatus and endoplasmic reticulum, as mediator of radioresistance. Downregulation of endogenous syntaxin 18 specifically reduced clonogenic survival of radioresistant and radiosensitive lung cancer cells following X-radiation. Gene expression programs regulating DNA repair, mitotic checkpoints and mitosis were altered in isogenic cells with reduced syntaxin 18 expression. Functionally, this translated into impaired DNA damage-induced cell cycle checkpoints leading to cell death by mitotic catastrophe. Interestingly, downregulation of syntaxin 18 in lung cancer cells also impaired expression of markers of epithelial-mesenchymal-transition, and reduced migration and invasion capacity. These findings suggest that syntaxin 18 is a key player regulating genes responsible for controlling the growth of the primary tumor as well as metastases upon radiotherapy of lung cancer. They provide a promising lead for biologically rational radiosensitization strategies impacting on radiation-induced cell death as well as metastasis. |
| first_indexed | 2024-04-12T18:07:12Z |
| format | Article |
| id | doaj.art-44dc9a67e42f49ab9888e498a0f3cf72 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-12T18:07:12Z |
| publishDate | 2022-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-44dc9a67e42f49ab9888e498a0f3cf722022-12-22T03:21:57ZengNature Publishing GroupCell Death and Disease2041-48892022-06-0113611110.1038/s41419-022-04978-4Syntaxin 18 regulates the DNA damage response and epithelial-to-mesenchymal transition to promote radiation resistance of lung cancerClotilde Thumser-Henner0Sebastian Oeck1Sophie Kalmbach2Jan Forster3Franziska Kindl4Ali Sak5Alexander Schramm6Martin Schuler7Laboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital EssenLaboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital EssenLaboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital EssenGerman Cancer Consortium (DKTK), Partner site University Hospital EssenLaboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital EssenDepartment of Radiotherapy, University Hospital EssenLaboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital EssenLaboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital EssenAbstract Radiotherapy is an important modality in lung cancer treatment. Despite advances in treatment planning and dose delivery, patient benefit is still limited by in-field relapse and metastatic recurrence. Simultaneous application of cisplatinum-based chemotherapy leads to moderately improved outcomes, thus providing proof-of-concept for radiosensitization strategies in lung cancer. In an unbiased functional genetic screen for radiosensitization targets in lung cancer, we identified syntaxin 18, a protein involved in retrograde vesicular transport between the Golgi apparatus and endoplasmic reticulum, as mediator of radioresistance. Downregulation of endogenous syntaxin 18 specifically reduced clonogenic survival of radioresistant and radiosensitive lung cancer cells following X-radiation. Gene expression programs regulating DNA repair, mitotic checkpoints and mitosis were altered in isogenic cells with reduced syntaxin 18 expression. Functionally, this translated into impaired DNA damage-induced cell cycle checkpoints leading to cell death by mitotic catastrophe. Interestingly, downregulation of syntaxin 18 in lung cancer cells also impaired expression of markers of epithelial-mesenchymal-transition, and reduced migration and invasion capacity. These findings suggest that syntaxin 18 is a key player regulating genes responsible for controlling the growth of the primary tumor as well as metastases upon radiotherapy of lung cancer. They provide a promising lead for biologically rational radiosensitization strategies impacting on radiation-induced cell death as well as metastasis.https://doi.org/10.1038/s41419-022-04978-4 |
| spellingShingle | Clotilde Thumser-Henner Sebastian Oeck Sophie Kalmbach Jan Forster Franziska Kindl Ali Sak Alexander Schramm Martin Schuler Syntaxin 18 regulates the DNA damage response and epithelial-to-mesenchymal transition to promote radiation resistance of lung cancer Cell Death and Disease |
| title | Syntaxin 18 regulates the DNA damage response and epithelial-to-mesenchymal transition to promote radiation resistance of lung cancer |
| title_full | Syntaxin 18 regulates the DNA damage response and epithelial-to-mesenchymal transition to promote radiation resistance of lung cancer |
| title_fullStr | Syntaxin 18 regulates the DNA damage response and epithelial-to-mesenchymal transition to promote radiation resistance of lung cancer |
| title_full_unstemmed | Syntaxin 18 regulates the DNA damage response and epithelial-to-mesenchymal transition to promote radiation resistance of lung cancer |
| title_short | Syntaxin 18 regulates the DNA damage response and epithelial-to-mesenchymal transition to promote radiation resistance of lung cancer |
| title_sort | syntaxin 18 regulates the dna damage response and epithelial to mesenchymal transition to promote radiation resistance of lung cancer |
| url | https://doi.org/10.1038/s41419-022-04978-4 |
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