FoxO3 reverses 5-fluorouracil resistance in human colorectal cancer cells by inhibiting the Nrf2/TR1 signaling pathway
FoxO3 reverses 5-fluorouracil resistance in human colorectal cancer cells by inhibiting the Nrf2/TR1 signaling pathway
复制标题
FoxO3通过抑制Nrf2/TR1信号通路逆转人结直肠癌细胞的5-氟尿嘧啶耐药性
DOI：
10.1016/j.canlet.2019.11.042
复制
发表时间：
2020-01-01
期刊：
影响因子：
9.7
通讯作者：
Du, Qianming
中科院分区：
文献类型：
--
作者：
Liu, Chao;Zhao, Yan;Du, Qianming
5-氟尿嘧啶（5-FU）广泛用于结直肠癌（CRC）的化疗，但较高的化疗耐药率降低了其临床治疗效果。我们发现，在 5-FU 耐药性 SW620 和 HCT-8（SW620/5-FU 和 HCT-8/5-FU）细胞中，叉头盒 3 (FoxO3) 蛋白（一种肿瘤抑制剂）的表达显着降低。此外，FoxO3 过表达使 SW620/5-FU 和 HCT-8/5-FU 细胞对 5-FU 敏感。从机制上来说，FoxO3 通过直接结合 Keap1 启动子来抑制核因子红细胞 2 相关因子 2 (Nrf2) 信号通路。据观察，硫氧还蛋白还原酶 1 (TR1) 是 Nrf2 的关键靶基因，可通过降低细胞内 ROS 水平来促进 5-FU 耐药性。临床数据还显示，TR1 的显着上调与 CRC 患者的不良预后相关。金诺芬 (AUR) 是一种 FoxO3 激动剂和 TR1 抑制剂，可在体外和体内增强 HCT-8/5-FU 和 SW620/5-FU 细胞对 5-FU 的敏感性。综上所述，我们的结果表明 FoxO3 可以通过抑制 Nrf2/TR1 信号通路并增加细胞内活性氧水平来逆转 CRC 中的 5-FU 耐药性。针对 FoxO3 和/或 TR1 的化疗药物（包括 AUR）可能是有前途的辅助增敏剂，可逆转 5-FU 耐药性结直肠癌的化疗耐药性。
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.