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

被引：57

作者：

Liu, Chao ^{[1
,2
,6
]}

Zhao, Yan ^{[2
,6
]}

Wang, Jianing ^{[3
]}

Yang, Yan ^{[4
,5
,12
]}

Zhang, Yan

Qu, Xinliang ^{[11
]}

Peng, Sishi ^{[1
,2
]}

Yao, Zhaoying ^{[2
,6
]}

Zhao, Shuli ^{[1
]}

He, Bangshun ^{[1
]}

Mi, Qiongyu ^{[1
]}

Zhu, Yubing ^{[2
,6
]}

Liu, Xiuting ^{[13
]}

Zou, Jianjun ^{[2
,6
]}

Zhang, Xu ^{[7
,8
,9
,10
]}

Du, Qianming ^{[1
,2
]}

机构：

[1] Nanjing Med Univ, Nanjing Hosp 1, Gen Clin Res Ctr, Nanjing 210006, Peoples R China

[2] China Pharmaceut Univ, Sch Basic Med & Clin Pharm, Dept Clin Pharm, Nanjing 210009, Peoples R China

[3] China Pharmaceut Univ, Jiangsu Ctr Drug Screening, Neurobiol Lab, Nanjing 210009, Jiangsu, Peoples R China

[4] Southwest Jiaotong Univ, Peoples Hosp Chengdu 3, Dept Pharm, 82 Qing Long St, Chengdu 610031, Peoples R China

[5] Southwest Jiaotong Univ, Affiliated Hosp, 82 Qing Long St, Chengdu 610031, Peoples R China

[6] Nanjing Med Univ, Nanjing Hosp 1, Dept Pharm, Nanjing 210006, Peoples R China

[7] Chengdu Med Coll, Peoples Hosp Chengdu 1, Dept Pharm, 18 Wanxiong East Rd, Chengdu 610041, Peoples R China

[8] Chengdu Med Coll, Affiliated Hosp, 18 Wanxiong East Rd, Chengdu 610041, Peoples R China

[9] Western Med Chengdu Med Coll, Affiliated Hosp Integrated Tradit Chinese, 783 Xindu Ave, Chengdu 610031, Peoples R China

[10] Western Med Chengdu Univ TCM, Affiliated Hosp Integrated Tradit Chinese, 37,Twelve Bridges Rd, Chengdu 610031, Peoples R China

[11] Nanjing Med Univ, Nanjing Hosp 1, Dept Cardiol, Nanjing 210006, Peoples R China

[12] Nanjing Med Univ, Nanjing Hosp 1, Dept Gastroenterol, Nanjing 210006, Peoples R China

[13] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA

来源：

CANCER LETTERS | 2020年 / 470卷

基金：

中国国家自然科学基金;

关键词：

FoxO3; 5-Fluorouracil; Colorectal cancer cells; Chemoresistance; Nrf2; ANTICANCER ACTIVITY; GENE-EXPRESSION; STRESS-RESPONSE; ACTIVATION; AURANOFIN; DRUG; PROTEINS; KEAP1; MECHANISMS; CISPLATIN;

D O I：

10.1016/j.canlet.2019.11.042

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：29 / 42

页数：14

共 54 条

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