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

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

Author information

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.

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

PMID:
27255972
DOI:
10.1016/j.canlet.2016.05.032
[Indexed for MEDLINE]

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