FoxO3 reverses 5-fluorouracil resistance in human colorectal cancer cells by inhibiting the Nrf2/TR1 signaling pathway.
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.
['Liu|Chao|C|', 'Zhao|Yan|Y|', 'Wang|Jianing|J|', 'Yang|Yan|Y|', 'Zhang|Yan|Y|', 'Qu|Xinliang|X|', 'Peng|Sishi|S|', 'Yao|Zhaoying|Z|', 'Zhao|Shuli|S|', 'He|Bangshun|B|', 'Mi|Qiongyu|Q|', 'Zhu|Yubing|Y|', 'Liu|Xiuting|X|', 'Zou|Jianjun|J|', 'Zhang|Xu|X|', 'Du|Qianming|Q|']
D000818:Animals D000971:Antineoplastic Combined Chemotherapy Protocols D001310:Auranofin D045744:Cell Line, Tumor D015179:Colorectal Neoplasms D019008:Drug Resistance, Neoplasm D005472:Fluorouracil D000071316:Forkhead Box Protein O3 D015972:Gene Expression Regulation, Neoplastic D006801:Humans D053208:Kaplan-Meier Estimate D000072019:Kelch-Like ECH-Associated Protein 1 D008297:Male D051379:Mice D051267:NF-E2-Related Factor 2 D011401:Promoter Regions, Genetic D017382:Reactive Oxygen Species D015398:Signal Transduction D054481:Thioredoxin Reductase 1 D015854:Up-Regulation D023041:Xenograft Model Antitumor Assays
FoxO3 5-Fluorouracil Colorectal cancer cells Nrf2 Chemoresistance