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.
复制标题
腺嘌呤核苷酸转位酶-1的构象变化介导EBV-LMP1诱导的顺铂耐药
DOI：
10.15252/emmm.202114072
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发表时间：
2021-12-07
影响因子：
11.1
通讯作者：
Cao Y
中科院分区：
文献类型：
--
作者：
Zhao L;Deng X;Li Y;Hu J;Xie L;Shi F;Tang M;Bode AM;Zhang X;Liao W;Cao Y
腺嘌呤核苷酸转位酶-1（ANT 1）是一种位于线粒体内膜的ADP/ATP转运蛋白。ANT 1不仅参与ADP/ATP交换过程，还参与线粒体膜通透性转换孔（mPTP）的组成，其功能与自身构象变化密切相关。值得注意的是，各种病毒蛋白可以直接与ANT 1相互作用，通过调节mPTP的开放来影响线粒体膜电位，从而影响肿瘤细胞的命运。EB病毒（EBV）编码的关键致瘤蛋白，潜伏膜蛋白1（LMP 1），它在促进相关肿瘤的治疗耐药性中起着关键作用。在我们的研究中，我们确定了鼻咽癌顺铂耐药中EBV-LMP 1诱导的ANT 1构象改变的新机制。在这里，我们发现EBV-LMP 1定位于线粒体内膜，并通过与ANT 1结合来抑制mPTP的开放，从而有利于肿瘤细胞的存活和耐药性。ANT 1构象抑制剂羧甲基纤维素苷（CATR）与顺铂的组合改善了EBV-LMP 1阳性细胞的化学敏感性。这一发现证实了ANT 1是未来克服顺铂耐药性的新治疗靶点。EB病毒编码的致瘤蛋白LMP 1调节线粒体蛋白腺噪呤核苷酸移位酶-1（ANT 1）的构象变化，从而调节肿瘤细胞的化疗耐药性。
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. EBV‐encoded tumorigenic protein LMP1 regulates conformational changes of mitochondrial protein adenine nucleotide translocase‐1 (ANT1), and thereby chemoresistance of tumor cells.