FOXM1 evokes 5-fluorouracil resistance in colorectal cancer depending on ABCC10

Oncotarget. 2017 Jan 31;8(5):8574-8589. doi: 10.18632/oncotarget.14351.

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.

Keywords: 5-FU; FOXM1; chemoresistance; colorectal cancer.

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology*
  • Apoptosis / drug effects*
  • Binding Sites
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm* / genetics
  • Fluorouracil / pharmacology*
  • Forkhead Box Protein M1 / antagonists & inhibitors
  • Forkhead Box Protein M1 / genetics
  • Forkhead Box Protein M1 / metabolism*
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Mice, Inbred BALB C
  • Mice, Nude
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Promoter Regions, Genetic
  • RNA Interference
  • Signal Transduction / drug effects
  • Thiostrepton / pharmacology
  • Time Factors
  • Transcription, Genetic
  • Transfection
  • Xenograft Model Antitumor Assays

Substances

  • ABCC10 protein, human
  • Antimetabolites, Antineoplastic
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Multidrug Resistance-Associated Proteins
  • Thiostrepton
  • Fluorouracil