EBV-LMP1 suppresses the DNA damage response through DNA-PK/AMPK signaling to promote radioresistance in nasopharyngeal carcinoma

Jingchen Lu; Min Tang; Hongde Li; Zhijie Xu; Xinxian Weng; Jiangjiang Li; Xinfang Yu; Luqing Zhao; Hongwei Liu; Yongbin Hu; Zheqiong Tan; Lifang Yang; Meizuo Zhong; Jian Zhou; Jia Fan; Ann M Bode; Wei Yi; Jinghe Gao; Lunquan Sun; Ya Cao

doi:10.1016/j.canlet.2016.05.032

EBV-LMP1 suppresses the DNA damage response through DNA-PK/AMPK signaling to promote radioresistance in nasopharyngeal carcinoma

Cancer Lett. 2016 Sep 28;380(1):191-200. doi: 10.1016/j.canlet.2016.05.032. Epub 2016 May 30.

Authors

Jingchen Lu¹, Min Tang², Hongde Li², Zhijie Xu², Xinxian Weng², Jiangjiang Li², Xinfang Yu³, Luqing Zhao⁴, Hongwei Liu⁵, Yongbin Hu⁴, Zheqiong Tan², Lifang Yang⁶, Meizuo Zhong⁷, Jian Zhou⁸, Jia Fan⁸, Ann M Bode⁹, Wei Yi², Jinghe Gao², Lunquan Sun¹⁰, Ya Cao¹¹

Affiliations

¹ Department of Medical Oncology, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.
² Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.
³ Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
⁴ Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.
⁵ Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
⁶ Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China; Molecular Imaging Center, Central South University, Changsha, China.
⁷ Department of Medical Oncology, Xiangya Hospital, Central South University, Changsha, China.
⁸ Key Laboratory of Chinese Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China.
⁹ The Hormel Institute, University of Minnesota, Austin, MN, USA.
¹⁰ Molecular Imaging Center, Central South University, Changsha, China.
¹¹ Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China; Molecular Imaging Center, Central South University, Changsha, China. Electronic address: ycao98@vip.sina.com.

PMID: 27255972
DOI: 10.1016/j.canlet.2016.05.032

Abstract

We conducted this research to explore the role of latent membrane protein 1 (LMP1) encoded by the Epstein-Barr virus (EBV) in modulating the DNA damage response (DDR) and its regulatory mechanisms in radioresistance. Our results revealed that LMP1 repressed the repair of DNA double strand breaks (DSBs) by inhibiting DNA-dependent protein kinase (DNA-PK) phosphorylation and activity. Moreover, LMP1 reduced the phosphorylation of AMP-activated protein kinase (AMPK) and changed its subcellular location after irradiation, which appeared to occur through a disruption of the physical interaction between AMPK and DNA-PK. The decrease in AMPK activity was associated with LMP1-mediated glycolysis and resistance to apoptosis induced by irradiation. The reactivation of AMPK significantly promoted radiosensitivity both in vivo and in vitro. The AMPKα (Thr172) reduction was associated with a poorer clinical outcome of radiation therapy in NPC patients. Our data revealed a new mechanism of LMP1-mediated radioresistance and provided a mechanistic rationale in support of the use of AMPK activators for facilitating NPC radiotherapy.

Keywords: AMPK; DNA damage response; DNA-PK; LMP1; Nasopharyngeal carcinoma.

MeSH terms

AMP-Activated Protein Kinases / metabolism*
Animals
Apoptosis / radiation effects
Carcinoma / enzymology
Carcinoma / pathology
Carcinoma / radiotherapy*
Carcinoma / virology
Cell Line, Tumor
DNA Breaks, Double-Stranded*
DNA Repair
DNA-Activated Protein Kinase / metabolism*
Dose-Response Relationship, Radiation
Enzyme Activation
Epstein-Barr Virus Infections / virology*
Female
Glycolysis
Herpesvirus 4, Human / metabolism*
Host-Pathogen Interactions
Humans
Mice, Inbred BALB C
Mice, Nude
Nasopharyngeal Carcinoma
Nasopharyngeal Neoplasms / enzymology
Nasopharyngeal Neoplasms / pathology
Nasopharyngeal Neoplasms / radiotherapy*
Nasopharyngeal Neoplasms / virology
Nuclear Proteins / metabolism*
Phosphorylation
Radiation Tolerance*
Signal Transduction / radiation effects
Time Factors
Tumor Burden / radiation effects
Viral Matrix Proteins / metabolism*
Xenograft Model Antitumor Assays

Substances

EBV-associated membrane antigen, Epstein-Barr virus
Nuclear Proteins
Viral Matrix Proteins
DNA-Activated Protein Kinase
PRKDC protein, human
AMP-Activated Protein Kinases