Tsuchida Kouhei, Tsujita Tadayuki, Hayashi Makiko, Ojima Asaka, Keleku-Lukwete Nadine, Katsuoka Fumiki, Otsuki Akihito, Kikuchi Haruhisa, Oshima Yoshiteru, Suzuki Mikiko, Yamamoto Masayuki
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; Department of Applied Biochemistry and Food Science, Saga University, Saga 840-8502, Japan.
Free Radic Biol Med. 2017 Feb;103:236-247. doi: 10.1016/j.freeradbiomed.2016.12.041. Epub 2016 Dec 28.
The KEAP1-NRF2 system regulates the cellular defence against oxidative and xenobiotic stresses. NRF2 is a transcription factor that activates the expression of cytoprotective genes encoding antioxidative, detoxifying and metabolic enzymes as well as transporters. Under normal conditions, KEAP1 represses NRF2 activity by degrading the NRF2 protein. When cells are exposed to stresses, KEAP1 stops promoting NRF2 degradation, and NRF2 rapidly accumulates and activates the transcription of target genes. Constitutive accumulation of NRF2 via a variety of mechanisms that disrupt KEAP1-mediated NRF2 degradation has been observed in various cancer types. Constitutive NRF2 accumulation confers cancer cells with a proliferative advantage as well as resistance to anti-cancer drugs and radiotherapies. To suppress the chemo- and radio-resistance of cancer cells caused by NRF2 accumulation, we conducted high-throughput chemical library screening for NRF2 inhibitors and identified febrifugine derivatives. We found that application of the less-toxic derivative halofuginone in a low dose range rapidly reduced NRF2 protein levels. Halofuginone induced a cellular amino acid starvation response that repressed global protein synthesis and rapidly depleted NRF2. Halofuginone treatment ameliorated the resistance of NRF2-addicted cancer cells to anti-cancer drugs both in vitro and in vivo. These results provide preclinical proof-of-concept evidence for halofuginone as an NRF2 inhibitor applicable to treatment of chemo- and radio-resistant forms of cancer.
KEAP1-NRF2系统调节细胞对氧化应激和外源性应激的防御。NRF2是一种转录因子，可激活编码抗氧化、解毒和代谢酶以及转运蛋白的细胞保护基因的表达。在正常情况下，KEAP1通过降解NRF2蛋白来抑制NRF2活性。当细胞受到应激时，KEAP1停止促进NRF2降解，NRF2迅速积累并激活靶基因的转录。在各种癌症类型中，已观察到通过多种破坏KEAP1介导的NRF2降解的机制导致NRF2组成性积累。NRF2的组成性积累赋予癌细胞增殖优势以及对抗癌药物和放射疗法的抗性。为了抑制由NRF2积累引起的癌细胞的化学抗性和放射抗性，我们对NRF2抑制剂进行了高通量化学文库筛选，并鉴定出了青蒿素衍生物。我们发现，应用低毒衍生物卤夫酮在低剂量范围内可迅速降低NRF2蛋白水平。卤夫酮诱导细胞氨基酸饥饿反应，抑制整体蛋白质合成并迅速消耗NRF2。卤夫酮处理改善了NRF2依赖性癌细胞在体外和体内对抗癌药物的抗性。这些结果为卤夫酮作为一种适用于治疗化学抗性和放射抗性癌症形式的NRF2抑制剂提供了临床前概念验证证据。
