MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma
| Autor: | Marc Barry, Antonio Jimeno, Sebastian Restrepo Cruz, Ellen J. Beswick, A. Cowan, Michelle A. Ozbun, Dennis J. McCance, Michael D Hixon, Stephen B. Keysar, Jacqueline James, Stephanie G Craig, Gregory N Gan, Kiersten L. Berggren |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_treatment Cell Apoptosis Mice 0302 clinical medicine Tumor Cells Cultured Phosphorylation Papillomaviridae Heat-Shock Proteins Tissue microarray biology Intracellular Signaling Peptides and Proteins Prognosis 3. Good health Gene Expression Regulation Neoplastic Survival Rate Cytokine medicine.anatomical_structure Head and Neck Neoplasms 030220 oncology & carcinogenesis Cytokines Female Epithelial-Mesenchymal Transition Mice Nude Protein Serine-Threonine Kinases Article 03 medical and health sciences Hsp27 SDG 3 - Good Health and Well-being Genetics medicine Biomarkers Tumor Gene silencing Animals Humans Molecular Biology Cell Proliferation Radiotherapy Cell growth Squamous Cell Carcinoma of Head and Neck Papillomavirus Infections medicine.disease Head and neck squamous-cell carcinoma Xenograft Model Antitumor Assays Radiation therapy 030104 developmental biology biology.protein Cancer research Follow-Up Studies Molecular Chaperones |
| Zdroj: | Berggren, K L, Restrepo Cruz, S, Hixon, M D, Cowan, A T, Keysar, S B, Craig, S, James, J, Barry, M, Ozbun, M A, Jimeno, A, McCance, D J, Beswick, E J & Gan, G N 2019, ' MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma ', Oncogene, vol. 38, pp. 7329–7341 . https://doi.org/10.1038/s41388-019-0945-9 Oncogene |
| Popis: | Radiation therapy (RT) is a cornerstone of treatment in the management of head and neck squamous cell carcinomas (HNSCC), yet treatment failure and disease recurrence are common. The p38/MK2 pathway is activated in response to cellular stressors, including radiation, and promotes tumor inflammation in a variety of cancers. We investigated MK2 pathway activation in HNSCC and the interaction of MK2 and RT in vitro and in vivo. We used a combination of an oropharyngeal SCC tissue microarray, HNSCC cell lines, and patient-derived xenograft (PDX) tumor models to study the effect of RT on MK2 pathway activation and to determine how inhibition of MK2 by pharmacologic (PF-3644022) and genetic (siRNA) methods impacts tumor growth. We show that high phosphorylated MK2 (p-MK2) levels are associated with worsened disease-specific survival in p16-negative HNSCC patients. RT increased p-MK2 in both p16-positive, HPV-positive and p16-negative, HPV-negative HNSCC cell lines. Pharmacologic inhibition or gene silencing of MK2 in vitro abrogated RT-induced increases in p-MK2; inflammatory cytokine expression and expression of the downstream MK2 target, heat shock protein 27 (HSP27); and markers of epithelial-to-mesenchymal transition. Mouse PDX models treated with a combination of RT and MK2 inhibitor experienced decreased tumor growth and increased survival. Our results suggest that MK2 is a potential prognostic biomarker for head and neck cancer and that MK2 pathway activation can mediate radiation resistance in HNSCC. |
| Databáze: | OpenAIRE |
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