title: The FOXM1-ABCC5 axis contributes to paclitaxel resistance in nasopharyngeal carcinoma cells.
abstract: 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.
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China.|Department of Radiation Oncology, Tumor Hospital, Xinjiang Medical University, Urumqi, China.
authors.forename: Youxiang
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Qianling
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Tumor Research Institute, Central South University, Changsha, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China.
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Yu
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Youhong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Linglong
authors.initials: L
authors.lastname: Yin
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Yuchong
authors.initials: Y
authors.lastname: Peng
authors.affiliation: School of Pharmaceutical Science, Central South University, Changsha, China.
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: School of Pharmaceutical Science, Central South University, Changsha, China.
authors.forename: Jinping
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Xie
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Department of Otorhinolaryngology, The Third Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Guolin
authors.initials: G
authors.lastname: Tan
authors.affiliation: Department of Radiation Oncology, Tumor Hospital, Xinjiang Medical University, Urumqi, China.
authors.forename: Kurban
authors.initials: K
authors.lastname: Gulina
authors.affiliation: Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Gong
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Lunquan
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Xuegong
authors.initials: X
authors.lastname: Fan
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Li
mesh_terms: D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D000072278:Forkhead Box Protein M1 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage*; D015398:Signal Transduction
chemical_list: D000072278:Forkhead Box Protein M1; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; C120809:ABCC5 protein, human; C107585:FOXM1 protein, human