2. Academic Validation
  3. Conformational change of adenine nucleotide translocase-1 mediates cisplatin resistance induced by EBV-LMP1

Conformational change of adenine nucleotide translocase-1 mediates cisplatin resistance induced by EBV-LMP1

  • EMBO Mol Med. 2021 Dec 7;13(12):e14072. doi: 10.15252/emmm.202114072.
Lin Zhao 1 2 3,  Xiangying Deng 1 2 3,  Yueshuo Li 1 2 3,  Jianmin Hu 1 2 3,  Longlong Xie 1 2 3,  Feng Shi 1 2 3,  Min Tang 1 2 3,  Ann M Bode 4,  Xin Zhang 5,  Weihua Liao 6,  Ya Cao 1 2 3 7 8 9
Affiliations

Affiliations

  • 1 Key Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, China.
  • 2 Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, China.
  • 3 Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, China.
  • 4 The Hormel Institute, University of Minnesota, Austin, MN, USA.
  • 5 Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.
  • 6 Department of Radiology, Xiangya Hospital, Central South University, Changsha, China.
  • 7 Molecular Imaging Research Center of Central, South University, Changsha, China.
  • 8 Research Center for Technologies of Nucleic Acid-Based Diagnostics and Therapeutics Hunan Province, Changsha, China.
  • 9 National Joint Engineering Research Center for Genetic Diagnostics of Infectious Diseases and Cancer, Changsha, China.
PMID: 34755470 DOI: 10.15252/emmm.202114072
Abstract

Adenine nucleotide translocase-1 (ANT1) is an ADP/ATP transporter protein located in the inner mitochondrial membrane. ANT1 is involved not only in the processes of ADP/ATP exchange but also in the composition of the mitochondrial membrane permeability transition pore (mPTP); and the function of ANT1 is closely related to its own conformational changes. Notably, various Viral Proteins can interact directly with ANT1 to influence mitochondrial membrane potential by regulating the opening of mPTP, thereby affecting tumor cell fate. The Epstein-Barr virus (EBV) encodes the key tumorigenic protein, latent membrane protein 1 (LMP1), which plays a pivotal role in promoting therapeutic resistance in related tumors. In our study, we identified a novel mechanism for EBV-LMP1-induced alteration of ANT1 conformation in cisplatin resistance in nasopharyngeal carcinoma. Here, we found that EBV-LMP1 localizes to the inner mitochondrial membrane and inhibits the opening of mPTP by binding to ANT1, thereby favoring tumor cell survival and drug resistance. The ANT1 conformational inhibitor carboxyatractyloside (CATR) in combination with cisplatin improved the chemosensitivity of EBV-LMP1-positive cells. This finding confirms that ANT1 is a novel therapeutic target for overcoming cisplatin resistance in the future.

Keywords

ANT1; LMP1; chemosensitivity; conformational change; mitochondrial membrane potential.

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