MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma

Kiersten L. Berggren; Sebastian Restrepo Cruz; Michael D. Hixon; Andrew T. Cowan; Stephen B. Keysar; Stephanie Craig; Jacqueline James; Marc Barry; Michelle A. Ozbun; Antonio Jimeno; Dennis J. McCance; Ellen J. Beswick; Gregory N. Gan

doi:10.1038/s41388-019-0945-9

MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma

Kiersten L. Berggren, Sebastian Restrepo Cruz, Michael D. Hixon, Andrew T. Cowan, Stephen B. Keysar, Stephanie Craig, Jacqueline James, Marc Barry, Michelle A. Ozbun, Antonio Jimeno, Dennis J. McCance, Ellen J. Beswick, Gregory N. Gan

Internal Medicine

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

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.

Original language	English
Pages (from-to)	7329-7341
Number of pages	13
Journal	Oncogene
Volume	38
Issue number	48
DOIs	https://doi.org/10.1038/s41388-019-0945-9
State	Published - Nov 28 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.

Funding

Initial support with PDX generation was performed with the assistance from the University of New Mexico Cancer Center Animal Shared Resource funded by NCI 2P30 CA118100. We also wish to acknowledge UNM Cancer Center Biostatistics Core Facility for their statistical assistance. Acknowledgements Work supported in part by RSNA Foundation Research Scholar Grant, ACS-IRG (IRG-14-187-19), Dedicated Health Research Fund from the University of New Mexico School of Medicine (UNM RAC 2018), STI CRC (U19 AI 113187), and the NIH P30 Grant NCI P30CA118100. The research in this paper was supported by the Human Tissue Repository and Tissue Analysis Shared Resource, funded by the Department of Pathology and The University of New Mexico Comprehensive Cancer Center and NCI P30CA118100. Many of the images in this paper were generated in the University of New Mexico Cancer Center Fluorescence Microscopy Shared Resource with current funding from NCI 2P30 CA118100.

Funders	Funder number
STI CRC	U19 AI 113187
University of New Mexico Comprehensive Cancer Center
University of New Mexico Comprehensive Cancer Center
University of New Mexico School of Medicine
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	R01CA207051, NCI P30CA118100
RSNA Research and Education Foundation	IRG-14-187-19
New Mexico State University, New York University	RAC 2018

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41388-019-0945-9

Cite this

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, 38(48), 7329-7341. https://doi.org/10.1038/s41388-019-0945-9

@article{b553e739e79c4d58aac2931c969b57d6,

title = "MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma",

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.",

author = "Berggren, \{Kiersten L.\} and \{Restrepo Cruz\}, Sebastian and Hixon, \{Michael D.\} and Cowan, \{Andrew T.\} and Keysar, \{Stephen B.\} and Stephanie Craig and Jacqueline James and Marc Barry and Ozbun, \{Michelle A.\} and Antonio Jimeno and McCance, \{Dennis J.\} and Beswick, \{Ellen J.\} and Gan, \{Gregory N.\}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2019",

month = nov,

day = "28",

doi = "10.1038/s41388-019-0945-9",

language = "English",

volume = "38",

pages = "7329--7341",

number = "48",

}

Berggren, KL, Restrepo Cruz, S, Hixon, MD, Cowan, AT, Keysar, SB, Craig, S, James, J, Barry, M, Ozbun, MA, Jimeno, A, McCance, DJ, Beswick, EJ & Gan, GN 2019, 'MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma', Oncogene, vol. 38, no. 48, pp. 7329-7341. https://doi.org/10.1038/s41388-019-0945-9

TY - JOUR

T1 - MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma

AU - Berggren, Kiersten L.

AU - Restrepo Cruz, Sebastian

AU - Hixon, Michael D.

AU - Cowan, Andrew T.

AU - Keysar, Stephen B.

AU - Craig, Stephanie

AU - James, Jacqueline

AU - Barry, Marc

AU - Ozbun, Michelle A.

AU - Jimeno, Antonio

AU - McCance, Dennis J.

AU - Beswick, Ellen J.

AU - Gan, Gregory N.

PY - 2019/11/28

Y1 - 2019/11/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85070809064&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070809064&partnerID=8YFLogxK

U2 - 10.1038/s41388-019-0945-9

DO - 10.1038/s41388-019-0945-9

M3 - Article

C2 - 31417185

AN - SCOPUS:85070809064

SN - 0950-9232

VL - 38

SP - 7329

EP - 7341

JO - Oncogene

JF - Oncogene

IS - 48

ER -

MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this