FoxO3 reverses 5-fluorouracil resistance in human colorectal cancer cells by inhibiting the Nrf2/TR1 signaling pathway
| Autor: | Sishi Peng, Yan Zhao, Y. Yang, Jianjun Zou, Xiuting Liu, Yubing Zhu, Zhaoying Yao, Xinliang Qu, Qiongyu Mi, Shuli Zhao, Xu Zhang, Chao Liu, Qianming Du, Jianing Wang, Yan Zhang, Bangshun He |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Thioredoxin Reductase 1 Cancer Research Auranofin NF-E2-Related Factor 2 Colorectal cancer Kaplan-Meier Estimate Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation In vivo Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans Promoter Regions Genetic Kelch-Like ECH-Associated Protein 1 Chemistry Forkhead Box Protein O3 medicine.disease Xenograft Model Antitumor Assays KEAP1 Up-Regulation Gene Expression Regulation Neoplastic 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research FOXO3 Fluorouracil Signal transduction Colorectal Neoplasms Reactive Oxygen Species Intracellular Signal Transduction medicine.drug |
| Zdroj: | Cancer Letters. 470:29-42 |
| ISSN: | 0304-3835 |
| DOI: | 10.1016/j.canlet.2019.11.042 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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