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Cited by 74Telomeres, Telomerase, and SenescenceHead and Neck Cancer StudiesCancer, Hypoxia, and Metabolism

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Early senescence and production of senescence-associated cytokines are major determinants of radioresistance in head-and-neck squamous cell carcinoma

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Schoetz, Ulrike, Klein, Diana, Hess, Julia, Shnayien, Seyd, Spoerl, Steffen, Orth, Michael, Mutlu, Samet, Hennel, Roman, Sieber, Anja, Ganswindt, Ute, Luka, Benedikt, Thomsen, Andreas R., Unger, Kristian, Jendrossek, Verena, Zitzelsberger, Horst, Blüthgen, Nils, Belka, Claus, Unkel, Steffen, Klinger, Bertram, Lauber, Kirsten·2021·Cell Death & Disease
DOI 10.1038/s41419-021-04454-5PMC PMC8674332
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Abstract

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.

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  • Radiation has been shown to induce senescence in human head-and-neck squamous cell carcinoma-derived cells.

    “Radiation has been shown to induce senescence in human head- and- neck squamous cell carcinoma- derived cells 102 .”

    From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [102]

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References 62 · Cited by 74

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Metadata

Authors
Schoetz, U., Klein, D., Hess, J., Shnayien, S., Spoerl, S., Orth, M., Mutlu, S., Hennel, R., Sieber, A., Ganswindt, U., Luka, B., Thomsen, A. R., Unger, K., Jendrossek, V., Zitzelsberger, H., Blüthgen, N., Belka, C., Unkel, S., Klinger, B., & Lauber, K.
Affiliations
  • Essen University Hospital (DE)
  • Helmholtz Munich (DE)
  • LMU Klinikum (DE)
  • German Cancer Research Center (DE)
  • Humboldt-Universität zu Berlin (DE)
  • Innsbruck Medical University (AT)
  • University of Freiburg (DE)
  • Universitätsmedizin Göttingen (DE)
Corresponding author
Lauber, Kirsten
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2021-12-15
Volume
12
Issue
12
Pages
1162-1162
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-021-04454-5
PMC
PMC8674332
OpenAlex
W4200487776
Cited by
74
References
62
Citations by year
2026: 12 · 2025: 19 · 2024: 23 · 2023: 13 · 2022: 7
FWCI
7.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
  • Site cant be reached (submittedVersion, cc-by)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
Funders
  • Bundesministerium für Bildung und Forschung (02NUK024C, 02NUK047C, 02NUK047A, 02NUK047D, 02NUK047E, 02NUK061C, DKTK)
  • Deutsche Forschungsgemeinschaft (INST 409/22-1 FUGG, INST 409/20-1 FUGG, and INST 409/126-1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
radioresistance (biology), head and neck squamous cell carcinoma, cellular senescence, NF-κB signaling, chemokine ligands, metformin, DNA repair, clonogenic survival, paracrine signaling, treatment outcomes
MeSH terms
Squamous Cell Carcinoma of Head and Neck, Head and Neck Neoplasms, Humans, Ligands, Radiation Tolerance, Retrospective Studies, Gene Expression Regulation, Neoplastic, Cytokines, NF-kappa B, Cellular Senescence, Receptors, Interleukin-8B, Cell Line, Tumor

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