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

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.

腺嘌呤核苷酸转运蛋白1（Adenine nucleotide translocase-1，ANT1）是定位于线粒体内膜的ADP/ATP转运蛋白。ANT1不仅参与ADP/ATP交换过程，还参与构成线粒体膜通透性转换孔（mitochondrial membrane permeability transition pore，mPTP）；其功能与自身构象变化密切相关。值得注意的是，多种病毒蛋白可直接与ANT1结合，通过调控mPTP的开放影响线粒体膜电位，进而影响肿瘤细胞的命运。EB病毒（Epstein-Barr virus，EBV）编码关键致瘤蛋白潜伏膜蛋白1（latent membrane protein 1，LMP1），该蛋白在促进相关肿瘤治疗耐药中发挥关键作用。本研究揭示了EBV-LMP1诱导鼻咽癌顺铂耐药过程中ANT1构象改变的全新机制。本研究发现，EBV-LMP1可定位于线粒体内膜，并通过结合ANT1抑制mPTP的开放，从而促进肿瘤细胞存活并增强其耐药性。联合使用ANT1构象抑制剂羧基苍术苷（carboxyatractyloside，CATR）与顺铂，可提高EBV-LMP1阳性细胞的化疗敏感性。本研究证实，ANT1有望成为未来克服顺铂耐药的新型治疗靶点。