Annexin A4 induces platinum resistance in a chloride-and calcium-dependent manner.
Annexin A4 induces platinum resistance in a chloride-and calcium-dependent manner.
复制标题
DOI：
10.18632/oncotarget.2306
复制
发表时间：
2014-09-15
期刊：
影响因子：
--
通讯作者：
Naka T
中科院分区：
文献类型：
--
作者：
Morimoto A;Serada S;Enomoto T;Kim A;Matsuzaki S;Takahashi T;Ueda Y;Yoshino K;Fujita M;Fujimoto M;Kimura T;Naka T
铂耐药性长期以来一直是各种癌症治疗中的主要问题。我们以前报道过，增强膜联蛋白A4（ANXA 4）的表达，钙调节的磷脂结合蛋白，诱导铂类药物的耐药性。在这项研究中，我们研究了膜联蛋白重复序列的作用，这是所有膜联蛋白家族的保守结构，负责铂抗性以及ANXA 4敲低的影响。ANXA4敲除增加了体外和体内对铂类药物的敏感性。为了鉴定负责化学抗性的结构域，通过从C末端一个接一个地删除膜联蛋白重复序列来构建ANXA 4缺失突变体。铂耐药诱导在体外和体内的细胞表达全长ANXA 4或缺失突变体，含有至少一个完整的膜联蛋白重复。然而，细胞表达的突变体没有任何钙结合位点的膜联蛋白重复序列，这是必不可少的ANXA 4易位从胞质溶胶到质膜，未能获得铂电阻。顺铂处理后，细胞内氯离子浓度，其通道部分由ANXA 4调节，显着增加铂耐药细胞。这些研究结果表明，钙结合位点的膜联蛋白重复诱导化疗耐药性铂类药物通过升高细胞内氯离子浓度。
Platinum resistance has long been a major issue in the treatment of various cancers. We previously reported that enhanced annexin A4 (ANXA4) expression, a Ca2+-regulated phospholipid-binding protein, induces chemoresistance to platinum-based drugs. In this study, we investigated the role of annexin repeats, a conserved structure of all the annexin family, responsible for platinum-resistance as well as the effect of knockdown of ANXA4. ANXA4 knockdown increased sensitivity to platinum-based drugs both in vitro and in vivo. To identify the domain responsible for chemoresistance, ANXA4 deletion mutants were constructed by deleting annexin repeats one by one from the C terminus. Platinum resistance was induced both in vitro and in vivo in cells expressing either full-length ANXA4 or the deletion mutants, containing at least one intact annexin repeat. However, cells expressing the mutant without any calcium-binding sites in the annexin repeated sequence, which is essential for ANXA4 translocation from the cytosol to plasma membrane, failed to acquire platinum resistance. After cisplatin treatment, the intracellular chloride ion concentration, whose channel is partly regulated by ANXA4, significantly increased in the platinum-resistant cells. These findings indicate that the calcium-binding site in the annexin repeat induces chemoresistance to the platinum-based drug by elevating the intracellular chloride concentration.
登录
查看更多内容
影响因子：
8
作者：
Al-Bahlani, S.;Fraser, M.;Wong, A. Y. C.;Sayan, B. S.;Bergeron, R.;Melino, G.;Tsang, B. K.
通讯作者：
Tsang, B. K.
影响因子：
3.3
作者：
Choi, Chel Hun;Sung, Chang Ohk;Kim, Byoung-Gie
通讯作者：
Kim, Byoung-Gie
影响因子：
6.5
作者：
Liedert, B;Materna, V;Lage, H
通讯作者：
Lage, H
影响因子：
8.8
作者：
Duncan, R.;Carpenter, B.;Main, L. C.;Telfer, C.;Murray, G. I.
通讯作者：
Murray, G. I.
影响因子：
1.5
作者：
Bookman, Michael A.
通讯作者：
Bookman, Michael A.