Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Cell Proliferation
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Cytokines / metabolism*
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Epithelial-Mesenchymal Transition
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Female
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Follow-Up Studies
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Gene Expression Regulation, Neoplastic
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Head and Neck Neoplasms / metabolism
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Head and Neck Neoplasms / pathology*
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Head and Neck Neoplasms / radiotherapy
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Head and Neck Neoplasms / virology
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Intracellular Signaling Peptides and Proteins / metabolism
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Mice
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Mice, Nude
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Molecular Chaperones / genetics
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Molecular Chaperones / metabolism
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Papillomaviridae / isolation & purification
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Papillomavirus Infections / complications*
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Papillomavirus Infections / virology
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Phosphorylation
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Prognosis
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Radiotherapy / methods*
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Squamous Cell Carcinoma of Head and Neck / metabolism
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Squamous Cell Carcinoma of Head and Neck / pathology*
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Squamous Cell Carcinoma of Head and Neck / radiotherapy
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Squamous Cell Carcinoma of Head and Neck / virology
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Survival Rate
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Biomarkers, Tumor
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Cytokines
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HSPB1 protein, human
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Heat-Shock Proteins
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Intracellular Signaling Peptides and Proteins
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Molecular Chaperones
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases