Gene silencing of indoleamine 2,3-dioxygenase 2 in melanoma cells induces apoptosis through the suppression of NAD+ and inhibits in vivo tumor growth.
Gene silencing of indoleamine 2,3-dioxygenase 2 in melanoma cells induces apoptosis through the suppression of NAD+ and inhibits in vivo tumor growth.
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DOI：
10.18632/oncotarget.8617
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发表时间：
2016-05-31
期刊：
影响因子：
--
通讯作者：
Min W
中科院分区：
文献类型：
--
作者：
Liu Y;Zhang Y;Zheng X;Zhang X;Wang H;Li Q;Yuan K;Zhou N;Yu Y;Song N;Fu J;Min W
吲哚胺2,3-双加氧酶2 （IDO2）是一种新发现的酶，催化色氨酸降解的初始和限速步骤。IDO2作为IDO1的同源蛋白，在T细胞增殖中起抑制作用，是健康条件下调节性T细胞（Treg）生成所必需的。IDO2的免疫非依赖性功能及其对癌细胞生理和病理生理的特殊贡献尚不清楚。本研究的目的是在小鼠模型中评估IDO2基因沉默作为抑制B16-BL6癌细胞的方法的影响。在这里，我们首次在体外证明，使用小干扰RNA （siRNA）敲除IDO2可抑制癌细胞增殖，阻滞G1细胞周期，诱导更大的细胞凋亡，并减少细胞迁移。IDO2的下调减少了烟酰胺腺嘌呤二核苷酸（NAD+）的产生，同时增加了活性氧（ROS）的产生。我们进一步证明，IDO2下调诱导的细胞凋亡可以通过添加外源性NAD+而减弱，这表明IDO2通过其代谢产物NAD+促进肿瘤生长的新机制。除了体外研究结果外，我们还证明了在肿瘤细胞中使用短发夹RNA （shRNA）沉默IDO2可以延缓肿瘤的形成，并在体内抑制肿瘤的生长。总之，本研究揭示了体外IDO2非免疫相关的新机制，B16-BL6细胞中IDO2的表达参与了肿瘤的发生和发展。我们的研究为基因沉默的新靶点提供了证据，该靶点具有增强癌症治疗的潜力。
Indoleamine 2,3-dioxygenase 2 (IDO2) is a newly discovered enzyme that catalyzes the initial and rate-limiting step in the degradation of tryptophan. As a homologous protein of IDO1, IDO2 plays an inhibitory role in T cell proliferation, and it is essential for regulatory T cell (Treg) generation in healthy conditions. Little is known about the immune-independent functions of IDO2 relevant to its specific contributions to physiology and pathophysiology in cancer cells. The purpose of this study was to assess the impact of IDO2 gene silencing as a way to inhibit B16-BL6 cancer cells in a murine model. Here, for the first time, we show that knockdown of IDO2 using small interfering RNA (siRNA) inhibits cancer cell proliferation, arrests cell cycle in G1, induces greater cell apoptosis, and reduces cell migration in vitro. Knockdown of IDO2 decreased the generation of nicotinamide adenine dinucleotide (NAD+) while increasing the generation of reactive oxygen species (ROS). We further demonstrate that cell apoptosis, induced by IDO2 downregulation, can be weakened by addition of exogenous NAD+, suggesting a novel mechanism by which IDO2 promotes tumor growth through its metabolite product NAD+. In addition to in vitro findings, we also demonstrate that IDO2 silencing in tumor cells using short hairpin RNA (shRNA) delayed tumor formation and arrested tumor growth in vivo. In conclusion, this study demonstrates a new non-immune-associated mechanism of IDO2 in vitro and IDO2 expression in B16-BL6 cells contributes to cancer development and progression. Our research provides evidence of a novel target for gene silencing that has the potential to enhance cancer therapy.
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影响因子：
8.8
作者：
Holmgaard RB;Zamarin D;Li Y;Gasmi B;Munn DH;Allison JP;Merghoub T;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
5.8
作者：
Loeb, Stefan;Koenigsrainer, Alfred;Terness, Peter
通讯作者：
Terness, Peter
影响因子：
11.2
作者：
Hou, De-Yan;Muller, Alexander J.;Munn, David H.
通讯作者：
Munn, David H.
影响因子：
6.4
作者：
Lee, GK;Park, HJ;Mellor, AL
通讯作者：
Mellor, AL
DOI：
10.1111/j.1533-869x.2003.01108.x
发表时间：
2003-11-01
影响因子：
--
作者：
Kai, Seiichiro;Goto, Shigeru;Kitano, Seigo
通讯作者：
Kitano, Seigo