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

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)191-200
Number of pages10
JournalCancer Letters
Volume380
Issue number1
DOIs
StatePublished - Sep 28 2016

Keywords

  • AMPK
  • DNA damage response
  • DNA-PK
  • LMP1
  • Nasopharyngeal carcinoma

Fingerprint Dive into the research topics of 'EBV-LMP1 suppresses the DNA damage response through DNA-PK/AMPK signaling to promote radioresistance in nasopharyngeal carcinoma'. Together they form a unique fingerprint.

Cite this