title: FOXM1 evokes 5-fluorouracil resistance in colorectal cancer depending on ABCC10.
abstract: 5-Fluorouracil (5-FU) is the most commonly used chemotherapeutic agent for colorectal cancer (CRC). However, frequently occurred 5-FU resistance poses a great challenge in the clinic. Elucidating the underlying mechanisms and developing effective strategies against 5-FU resistance are highly desired. Here we identified the upregulation of FOXM1 in 5-FU nonresponsive CRC patients by gene expression profile analysis and 5-FU-resistant CRC cells by qRT-PCR assay. Silencing of FOXM1 promoted the sensitivity of CRC cells to 5-FU by enhancing cell apoptosis, while overexpression of FOXM1 conferred CRC cells with 5-FU resistance both in vitro and in vivo. Furthermore, we showed that genetic and pharmacological inhibition of FOXM1 resensitized resistant CRC cells to 5-FU treatment. Mechanistically, FOXM1 promoted the transcription of ABCC10 by directly binding to its promoter region. Notably, treatment with ABCC10 inhibitor reversed FOXM1-induced resistance to 5-FU in vivo. Clinical investigation revealed that the levels of FOXM1 and ABCC10 were positively correlated in CRC tissues. Therefore, FOXM1 promotes 5-FU resistance by upregulating ABCC10, suggesting that FOXM1/ABCC10 axis may serve as a potential therapeutic target for 5-FU resistance in CRC patients.
authors.affiliation: Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing 210002, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.affiliation: Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing 210002, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Geng
authors.affiliation: Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing 210002, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.
authors.forename: Liya
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.
authors.forename: Mengxi
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Xue
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Mao
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Dai
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Ren
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.
authors.forename: Hongju
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.
authors.forename: Longbang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing 210002, China.|Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing 210002, China.|Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chu
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology*; D000072278:Forkhead Box Protein M1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013883:Thiostrepton / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil; D000072278:Forkhead Box Protein M1; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D013883:Thiostrepton; C421142:ABCC10 protein, human; C107585:FOXM1 protein, human
keywords: 5-FU; FOXM1; chemoresistance; colorectal cancer