The FOXM1-ABCC5 axis contributes to paclitaxel resistance in nasopharyngeal carcinoma cells.
The FOXM1-ABCC5 axis contributes to paclitaxel resistance in nasopharyngeal carcinoma cells.
复制标题
FOXM1-ABCC5 轴导致鼻咽癌细胞对紫杉醇产生耐药性。
DOI：
10.1038/cddis.2017.53
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发表时间：
2017-03-09
影响因子：
9
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Hou Y;Zhu Q;Li Z;Peng Y;Yu X;Yuan B;Liu Y;Liu Y;Yin L;Peng Y;Jiang Z;Li J;Xie B;Duan Y;Tan G;Gulina K;Gong Z;Sun L;Fan X;Li X
紫杉醇在临床上用作几种癌症类型的一线化疗方案，包括头颈癌。然而，获得性耐药导致治疗失败、转移和复发。由ATP结合盒（ABC）转运蛋白介导的药物外排和由叉头盒（FOX）分子激活的生存信号在紫杉醇耐药的发展中起着至关重要的作用。FOX分子是否通过药物外排促进紫杉醇耐药性仍不清楚。在这项研究中，我们开发了几种类型的紫杉醇耐药（TR）鼻咽癌（NPC）细胞。这些TR NPC细胞获得癌干细胞（CSC）表型，并经历上皮间质转化（EMT），并产生多药耐药。TR细胞表现出比亲代NPC细胞更强的药物外排，导致细胞内药物浓度降低和药物不敏感。在筛选ABC转运蛋白和FOX分子的基因表达后，我们发现FOXM1和ABCC 5在TR NPC细胞和患者肿瘤组织中一致地过表达。进一步的研究表明，FOXM1通过与启动子上的FHK共有基序结合来调控abcc5基因的转录。用siRNA去除FOXM1或ABCC5显著阻断药物外排并增加紫杉醇的细胞内浓度，从而促进紫杉醇诱导的细胞死亡。FOXM1抑制剂Siomycin A可显著增强紫杉醇对耐药NPC细胞的体外杀伤作用。这项研究是第一个确定FOXM1在药物外排和紫杉醇耐药的作用，通过调节ABC转运蛋白之一的abcc5的基因转录。FOXM1或ABCC5的小分子抑制剂有可能克服NPC患者对紫杉醇的耐药性。
Paclitaxel is clinically used as a first-line chemotherapeutic regimen for several cancer types, including head and neck cancers. However, acquired drug resistance results in the failure of therapy, metastasis and relapse. The drug efflux mediated by ATP-binding cassette (ABC) transporters and the survival signals activated by forkhead box (FOX) molecules are critical in the development of paclitaxel drug resistance. Whether FOX molecules promote paclitaxel resistance through drug efflux remains unknown. In this study, we developed several types of paclitaxel-resistant (TR) nasopharyngeal carcinoma (NPC) cells. These TR NPC cells acquired cancer stem cell (CSC) phenotypes and underwent epithelial to mesenchymal transition (EMT), and developed multidrug resistance. TR cells exhibited stronger drug efflux than parental NPC cells, leading to the reduction of intracellular drug concentrations and drug insensitivity. After screening the gene expression of ABC transporters and FOX molecules, we found that FOXM1 and ABCC5 were consistently overexpressed in the TR NPC cells and in patient tumor tissues. Further studies demonstrated that FOXM1 regulated abcc5 gene transcription by binding to the FHK consensus motifs at the promoter. The depletion of FOXM1 or ABCC5 with siRNA significantly blocked drug efflux and increased the intracellular concentrations of paclitaxel, thereby promoting paclitaxel-induced cell death. Siomycin A, a FOXM1 inhibitor, significantly enhanced in vitro cell killing by paclitaxel in drug-resistant NPC cells. This study is the first to identify the roles of FOXM1 in drug efflux and paclitaxel resistance by regulating the gene transcription of abcc5, one of the ABC transporters. Small molecular inhibitors of FOXM1 or ABCC5 have the potential to overcome paclitaxel chemoresistance in NPC patients.