FoxO3 reverses 5-fluorouracil resistance in human colorectal cancer cells by inhibiting the Nrf2/TR1 signaling pathway

Chao Liu, Yan Zhao, Jianing Wang, Yan Yang, Yan Zhang, Xinliang Qu, Sishi Peng, Zhaoying Yao, Shuli Zhao, Bangshun He, Qiongyu Mi, Yubing Zhu, Xiuting Liu, Jianjun Zou, Xu Zhang, Qianming Du

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

5-fluorouracil (5-FU) is widely used in chemotherapy for colorectal cancer (CRC), but a high rate of chemoresistance reduces its effectiveness in clinical treatment. We found remarkably decreased expression of forkhead box 3 (FoxO3) protein, a tumor inhibitor, in 5-FU-resistant SW620 and HCT-8 (SW620/5-FU and HCT-8/5-FU) cells. Moreover, FoxO3 overexpression sensitized SW620/5-FU and HCT-8/5-FU cells to 5-FU. Mechanistically, FoxO3 inhibited the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway by directly binding to Keap1 promoter. Thioredoxin reductase 1 (TR1), a pivotal target gene of Nrf2, was observed to promote 5-FU resistance by reducing intracellular ROS levels. Clinical data also revealed that significant upregulation of TR1 was associated with poor outcome in CRC patients. Auranofin (AUR), a FoxO3 agonist and TR1 inhibitor, enhanced the sensitivity of HCT-8/5-FU and SW620/5-FU cells to 5-FU in vitro and in vivo. Taken together, our results suggest that FoxO3 could reverse 5-FU resistance in CRC via inhibiting the Nrf2/TR1 signaling pathway, and increasing the level of intracellular reactive oxygen species. Chemotherapeutic agents targeting FoxO3 and/or TR1, including AUR, might be promising adjuvant sensitizers to reverse chemoresistance in 5-FU-resistant CRC.

Original languageEnglish
Pages (from-to)29-42
Number of pages14
JournalCancer Letters
Volume470
DOIs
StatePublished - Feb 1 2020

Keywords

  • 5-Fluorouracil
  • Chemoresistance
  • Colorectal cancer cells
  • FoxO3
  • Nrf2

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