1-L-MT, an IDO inhibitor, prevented colitis-associated cancer by inducing CDC20 inhibition-mediated mitotic death of colon cancer cells
1-L-MT, an IDO inhibitor, prevented colitis-associated cancer by inducing CDC20 inhibition-mediated mitotic death of colon cancer cells
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DOI：
10.1002/ijc.31417
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发表时间：
2018-09-15
影响因子：
6.4
通讯作者：
Hu, Rong
中科院分区：
文献类型：
--
作者：
Liu, Xiuting;Zhou, Wei;Hu, Rong
吲哚胺2，3-双加氧酶1（IDO 1）通过犬尿氨酸途径分解代谢色氨酸，其活性与结直肠癌的临床结局受损相关。在这里，我们表明，1-L-MT，一个典型的IDO抑制剂，通过诱导有丝分裂死亡抑制人结肠直肠癌细胞的增殖。我们的研究结果表明，抑制IDO降低了CDC 20的转录，这导致HCT-116和HT-29的G2/M周期阻滞。此外，1-L-MT诱导线粒体损伤并引起癌细胞凋亡。重要的是，1-L-MT保护小鼠免受氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导的结肠癌发生，降低死亡率，肿瘤数量和大小。更重要的是，IDO 1-/-小鼠表现出更少的肿瘤负荷和减少的肿瘤上皮细胞增殖，而1-L-MT对IDO-/-小鼠没有表现出任何进一步的保护作用，证实了IDO的关键作用和1-LMT介导的IDO抑制在CRC中的保护作用。此外，1-L-MT还减轻Rag 1-/-小鼠中的CRC，证明IDO的调节作用独立于其在调节适应性免疫中的作用。综上所述，我们的研究结果证实，1-L-MT在体外的抗增殖作用和在体内的CRC预防是通过IDO诱导的结肠癌细胞的细胞周期灾难。我们的研究结果表明，1-L-MT作为一个有前途的候选人的化学预防CRC。
Indoleamine 2,3-dioxygenase 1 (IDO1), known as IDO, catabolizes tryptophan through kynurenine pathway, whose activity is correlated with impaired clinical outcome of colorectal cancer. Here we showed that 1-L-MT, a canonical IDO inhibitor, suppressed proliferation of human colorectal cancer cells through inducing mitotic death. Our results showed that inhibition of IDO decreased the transcription of CDC20, which resulted in G2/M cycle arrest of HCT-116 and HT-29. Furthermore, 1-L-MT induced mitochondria injuries and caused apoptotic cancer cells. Importantly, 1-L-MT protected mice from azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon carcinogenesis, with reduced mortality, tumor number and size. What is more, IDO1-/- mice exhibited fewer tumor burdens and reduced proliferation in the neoplastic epithelium, while, 1-L-MT did not exhibit any further protective effects on IDO-/- mice, confirming the critical role of IDO and the protective effect of 1-LMT-mediated IDO inhibition in CRC. Furthermore, 1-L-MT also alleviated CRC in Rag1-/- mice, demonstrating the modulatory effects of IDO independent of its role in modulating adaptive immunity. Taken together, our findings validated that the anti-proliferation effect of 1-L-MT in vitro and the prevention of CRC in vivo were through IDO-induced cell cycle disaster of colon cancer cells. Our results identified 1-L-MT as a promising candidate for the chemoprevention of CRC.