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Background <p>Radiation-induced senescence strongly contributes to therapy resistance in HPV-negative head and neck squamous cell carcinoma (HNSCC). In particular, the NF-<InlineEquation ID="IEq1"> <EquationSource Format="TEX">\({\rm{\kappa }}\)</EquationSource> </InlineEquation>B-dependent arm of the senescence-associated secretory phenotype (SASP) activates signaling pathways that are tightly associated with, and promote, resistance to irradiation. In addition to the SASP, another hallmark of senescence is the upregulation of anti-apoptotic proteins. The BH3-only mimetic ABT-263 has been shown to effectively eliminate senescent cells. In this study, we employed ABT-263 to overcome the therapy-induced resistance in HNSCC cells and uncovered a link to chemokine signaling.</p> Methods <p>The HNSCC cell lines Cal33 and UPCI:SCC040 were treated with a combination of ABT-263 and photon irradiation, followed by functional and mechanistic assays assessing viability, apoptosis, senescence, secreted proteins, clonogenic survival, and DNA repair.</p> Results <p>Functionally, ABT-263 induced apoptosis via impeding Bcl-xL and activating Bax. Senescence levels were reduced after irradiation. Mechanistically, we observed cell-line- and protein-specific changes in the SASP, including a striking difference in CXCR2 receptor expression. Cal33 cells exhibited strong downregulation of CXCR2 and were radiosensitized by ABT-263, as indicated by reduced viability and clonogenic survival. In contrast, CXCR2 expression was induced in UPCI:SCC040 cells following treatment; although viability was diminished, clonogenic survival remained unaffected. Notably, radiosensitization in UPCI:SCC040 cells could be achieved through concomitant inhibition of CXCR2. Furthermore, the radiosensitizing effect was not attributable to increased DNA damage, as evidenced by <InlineEquation ID="IEq2"> <EquationSource Format="TEX">\(\gamma \)</EquationSource> </InlineEquation>H2AX/53BP1 co-localization.</p> Conclusions <p>These findings highlight a central role for CXCR2-mediated signaling in the development of radioresistance in HPV-negative HNSCC cells.</p> Clinical trial number <p>Not applicable</p>

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CXCR2 affects sensitization of radioresistant HPV-negative head and neck squamous cell carcinoma cells by ABT-263

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月12日

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  • Sibylla Kohl,
  • Mareike Schaper,
  • José Arteaga Lajarín,
  • Florentine S. B. Subtil,
  • Rita Engenhart-Cabillic,
  • Ekkehard Dikomey,
  • Sebastian Adeberg,
  • Ulrike Theiß

摘要

Background

Radiation-induced senescence strongly contributes to therapy resistance in HPV-negative head and neck squamous cell carcinoma (HNSCC). In particular, the NF- \({\rm{\kappa }}\) B-dependent arm of the senescence-associated secretory phenotype (SASP) activates signaling pathways that are tightly associated with, and promote, resistance to irradiation. In addition to the SASP, another hallmark of senescence is the upregulation of anti-apoptotic proteins. The BH3-only mimetic ABT-263 has been shown to effectively eliminate senescent cells. In this study, we employed ABT-263 to overcome the therapy-induced resistance in HNSCC cells and uncovered a link to chemokine signaling.

Methods

The HNSCC cell lines Cal33 and UPCI:SCC040 were treated with a combination of ABT-263 and photon irradiation, followed by functional and mechanistic assays assessing viability, apoptosis, senescence, secreted proteins, clonogenic survival, and DNA repair.

Results

Functionally, ABT-263 induced apoptosis via impeding Bcl-xL and activating Bax. Senescence levels were reduced after irradiation. Mechanistically, we observed cell-line- and protein-specific changes in the SASP, including a striking difference in CXCR2 receptor expression. Cal33 cells exhibited strong downregulation of CXCR2 and were radiosensitized by ABT-263, as indicated by reduced viability and clonogenic survival. In contrast, CXCR2 expression was induced in UPCI:SCC040 cells following treatment; although viability was diminished, clonogenic survival remained unaffected. Notably, radiosensitization in UPCI:SCC040 cells could be achieved through concomitant inhibition of CXCR2. Furthermore, the radiosensitizing effect was not attributable to increased DNA damage, as evidenced by \(\gamma \) H2AX/53BP1 co-localization.

Conclusions

These findings highlight a central role for CXCR2-mediated signaling in the development of radioresistance in HPV-negative HNSCC cells.

Clinical trial number

Not applicable