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Cancer Lett. 2020 Feb 1;470:29-42. doi: 10.1016/j.canlet.2019.11.042. Epub 2019 Dec 4.

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

Author information

1
General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China; Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China; Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China.
2
Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China; Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
3
Neurobiology Laboratory, Jiangsu Center for Drug Screening, China Pharmaceutical University, Jiangsu, Nanjing, 210009, China.
4
Department of Pharmacy, The Third People's Hospital of Chengdu & Affiliated Hospital of Southwest Jiaotong University, 82 Qing Long Street, Chengdu, 610031, China.
5
Department of Gastroenterology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China.
6
Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China.
7
General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China; Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
8
General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China.
9
Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China; Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China.
10
Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
11
Department of Pharmacy, The First People's Hospital of Chengdu & Affiliated Hospital of Chengdu Medical College, 18# Wanxiang East Road, Chengdu, 610041, China; Affiliated Hospital of Integrated Traditional Chinese, Western Medicine of Chengdu Medical College, 783 Xindu Avenue, Chengdu, 610031, China; Affiliated Hospital of Integrated Traditional Chinese, Western Medicine of Chengdu University of TCM, 37#, Twelve Bridges Road, Chengdu, 610031, China.
12
General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China; Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: duqianming@njmu.edu.cn.

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.

KEYWORDS:

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

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