EBV-LMP1 promotes radioresistance by inducing protective autophagy through BNIP3 in nasopharyngeal carcinoma

Cell Death Dis. 2021 Apr 1;12(4):344. doi: 10.1038/s41419-021-03639-2.

Abstract

Studies have indicated that dysfunction of autophagy is involved in the initiation and progression of multiple tumors and their chemoradiotherapy. Epstein-Barr virus (EBV) is a lymphotropic human gamma herpes virus that has been implicated in the pathogenesis of nasopharyngeal carcinoma (NPC). EBV encoded latent membrane protein1 (LMP1) exhibits the properties of a classical oncoprotein. In previous studies, we experimentally demonstrated that LMP1 could increase the radioresistance of NPC. However, how LMP1 contributes to the radioresistance in NPC is still not clear. In the present study, we found that LMP1 could enhance autophagy by upregulating the expression of BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3). Knockdown of BNIP3 could increase the apoptosis and decrease the radioresistance mediated by protective autophagy in LMP1-positive NPC cells. The data showed that increased BNIP3 expression is mediated by LMP1 through the ERK/HIF1α signaling axis, and LMP1 promotes the binding of BNIP3 to Beclin1 and competitively reduces the binding of Bcl-2 to Beclin1, thus upregulating autophagy. Furthermore, knockdown of BNIP3 can reduce the radioresistance promoted by protective autophagy in vivo. These data clearly indicated that, through BNIP3, LMP1 induced autophagy, which has a crucial role in the protection of LMP1-positive NPC cells against irradiation. It provides a new basis and potential target for elucidating LMP1-mediated radioresistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology
  • Autophagy / physiology*
  • Cell Line, Tumor
  • Epstein-Barr Virus Infections / metabolism
  • Epstein-Barr Virus Infections / virology
  • Gene Expression Regulation, Neoplastic
  • Herpesvirus 4, Human / metabolism
  • Humans
  • Membrane Proteins / metabolism*
  • Nasopharyngeal Carcinoma / metabolism*
  • Nasopharyngeal Carcinoma / pathology
  • Nasopharyngeal Neoplasms / pathology
  • Proto-Oncogene Proteins / metabolism*
  • Viral Matrix Proteins / metabolism*

Substances

  • BNIP3 protein, human
  • EBV-associated membrane antigen, Epstein-Barr virus
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Viral Matrix Proteins