Early senescence and production of senescence-associated cytokines are major determinants of radioresistance in head-and-neck squamous cell carcinoma
| العنوان: | Early senescence and production of senescence-associated cytokines are major determinants of radioresistance in head-and-neck squamous cell carcinoma |
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| المؤلفون: | Ulrike Schoetz, Diana Klein, Julia Hess, Seyd Shnayien, Steffen Spoerl, Michael Orth, Samet Mutlu, Roman Hennel, Anja Sieber, Ute Ganswindt, Benedikt Luka, Andreas R. Thomsen, Kristian Unger, Verena Jendrossek, Horst Zitzelsberger, Nils Blüthgen, Claus Belka, Steffen Unkel, Bertram Klinger, Kirsten Lauber |
| المصدر: | Cell Death & Disease Cell Death and Disease, Vol 12, Iss 12, Pp 1-14 (2021) Cell Death Dis. 12:1162 (2021) |
| بيانات النشر: | Nature Publishing Group UK, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cancer Research, QH573-671, Radiotherapy, Squamous Cell Carcinoma of Head and Neck, Tumour heterogeneity, Immunology, Medizin, NF-kappa B, Cell Biology, Senescence, Ligands, Radiation Tolerance, Article, Receptors, Interleukin-8B, Gene Expression Regulation, Neoplastic, Cellular and Molecular Neuroscience, Head and Neck Neoplasms, Cell Line, Tumor, Cytokines, Humans, Cytology, Head and neck cancer, Cellular Senescence, Retrospective Studies |
| الوصف: | Resistance against radio(chemo)therapy-induced cell death is a major determinant of oncological treatment failure and remains a perpetual clinical challenge. The underlying mechanisms are manifold and demand for comprehensive, cancer entity- and subtype-specific examination. In the present study, resistance against radiotherapy was systematically assessed in a panel of human head-and-neck squamous cell carcinoma (HNSCC) cell lines and xenotransplants derived thereof with the overarching aim to extract master regulators and potential candidates for mechanism-based pharmacological targeting. Clonogenic survival data were integrated with molecular and functional data on DNA damage repair and different cell fate decisions. A positive correlation between radioresistance and early induction of HNSCC cell senescence accompanied by NF-κB-dependent production of distinct senescence-associated cytokines, particularly ligands of the CXCR2 chemokine receptor, was identified. Time-lapse microscopy and medium transfer experiments disclosed the non-cell autonomous, paracrine nature of these mechanisms, and pharmacological interference with senescence-associated cytokine production by the NF-κB inhibitor metformin significantly improved radiotherapeutic performance in vitro and in vivo. With regard to clinical relevance, retrospective analyses of TCGA HNSCC data and an in-house HNSCC cohort revealed that elevated expression of CXCR2 and/or its ligands are associated with impaired treatment outcome. Collectively, our study identifies radiation-induced tumor cell senescence and the NF-κB-dependent production of distinct senescence-associated cytokines as critical drivers of radioresistance in HNSCC whose therapeutic targeting in the context of multi-modality treatment approaches should be further examined and may be of particular interest for the subgroup of patients with elevated expression of the CXCR2/ligand axis. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2041-4889 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d6f7d5195960347d6a4004275107d245Test http://europepmc.org/articles/PMC8674332Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d6f7d5195960347d6a4004275107d245 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20414889 |
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