Intracellular calprotectin (S100A8/A9) facilitates DNA damage responses and promotes apoptosis in head and neck squamous cell carcinoma

Prokopios Argyris, Flávia Saavedra, Christopher R Malz, Ian A Stone, Yuping Wei, William S. Boyle, Karen F. Johnstone, Ali Khammanivong, Mark C. Herzberg

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Objectives: In head and neck squamous cell carcinoma (HNSCC), poor prognosis and low survival rates are associated with downregulated calprotectin. Calprotectin (S100A8/A9) inhibits cancer cell migration and invasion and facilitates G2/M cell cycle arrest. We investigated whether S100A8/A9 regulates DNA damage responses (DDR) and apoptosis in HNSCC after chemoradiation. Materials and methods: Human HNSCC cases in TCGA were analyzed for relationships between S100A8/A9 and expression of apoptosis-related genes. Next, S100A8/A9-expressing and non-expressing carcinoma lines (two different lineages) were exposed to genotoxic agents and assessed for 53BP1 and γH2AX expression and percent of viable/dead cells. Finally, S100A8/A9-wild-type and S100A8/A9null C57BL/6j mice were treated with 4-NQO to induce oral dysplastic and carcinomatous lesions, which were compared for levels of 53BP1. Results: In S100A8/A9-high HNSCC tumors, apoptosis-related caspase family member genes were upregulated, whereas genes limiting apoptosis were significantly downregulated based on TCGA analyses. After X-irradiation or camptothecin treatment, S100A8/A9-expressing carcinoma cells (i.e., TR146 and KB-S100A8/A9) showed significantly higher 53BP1 and γH2AX expression, DNA fragmentation, proportions of dead cells, and greater sensitivity to cisplatin than wild-type KB or TR146-S100A8/A9-KD cells. Interestingly, KB-S100A8/A9Δ113-114 cells showed similar 53BP1 and γH2AX levels to S100A8/A9-negative KB and KB-EGFP cells. After 4-NQO treatment, 53BP1 expression in oral lesions was significantly greater in calprotectin+/+ than S100A8/A9null mice. Conclusions: In HNSCC cells, intracellular calprotectin is strongly suggested to potentiate DDR and promote apoptosis in response to genotoxic agents. Hence, patients with S100A8/A9-high HNSCC may encounter more favorable outcomes because more tumor cells enter apoptosis with increased sensitivity to chemoradiation therapy.

Original languageEnglish (US)
Article number106304
JournalOral Oncology
Volume137
DOIs
StatePublished - Feb 2023

Bibliographical note

Funding Information:
The project was supported by NIH/NIDCR R01DE021206 to MCH and R90DE023058 to PPA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIDCR or the NIH. The authors thank Dr. Shorouk Elnagdy for assistance with the mice in the 4-NQO protocol, Drs. Rajaram Gopalakrishnan and Ioannis G. Koutlas, University of Minnesota, for assistance with mouse tissue processing for histopathologic analysis, and Dr. Gay Herzberg for expert editing.

Funding Information:
The project was supported by NIH/NIDCR R01DE021206 to MCH and R90DE023058 to PPA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIDCR or the NIH. The authors thank Dr. Shorouk Elnagdy for assistance with the mice in the 4-NQO protocol, Drs. Rajaram Gopalakrishnan and Ioannis G. Koutlas, University of Minnesota, for assistance with mouse tissue processing for histopathologic analysis, and Dr. Gay Herzberg for expert editing.

Publisher Copyright:
© 2022

Keywords

  • 53BP1
  • Calprotectin
  • Cisplatin
  • DNA damage
  • Double-strand breaks
  • Head and neck cancer
  • Head and neck squamous cell carcinoma
  • Radiation
  • S100A8/A9
  • γH2AX

Fingerprint

Dive into the research topics of 'Intracellular calprotectin (S100A8/A9) facilitates DNA damage responses and promotes apoptosis in head and neck squamous cell carcinoma'. Together they form a unique fingerprint.

Cite this