Oncotarget

Research Papers:

Gene silencing of indoleamine 2,3-dioxygenase 2 in melanoma cells induces apoptosis through the suppression of NAD+ and inhibits in vivo tumor growth

Yanling Liu, Yujuan Zhang, Xiufen Zheng, Xusheng Zhang, Hongmei Wang, Qin Li, Keng Yuan, Nanjing Zhou, Yanrong Yu, Na Song, Jiamin Fu and Weiping Min _

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Oncotarget. 2016; 7:32329-32340. https://doi.org/10.18632/oncotarget.8617

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Abstract

Yanling Liu1,2,3,4, Yujuan Zhang1,3, Xiufen Zheng4, Xusheng Zhang4, Hongmei Wang1, Qin Li1, Keng Yuan1,3, Nanjing Zhou1,3, Yanrong Yu1,3, Na Song1, Jiamin Fu1, Weiping Min1,3,4

1Institute of Immunotherapy of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China

2Jiangxi University of Technology, Nanchang, China

3Jiangxi Provincial Key Laboratory of Immunotherapy, Nanchang, China

4Department of Surgery, Pathology, and Oncology, University of Western Ontario, London, Canada

Correspondence to:

Yujuan Zhang, email: zyj900203@sina.com

Weiping Min, email: mweiping@uwo.ca

Keywords: IDO2, NAD+, apoptosis, neoplasm, siRNA

Received: December 13, 2015     Accepted: March 14, 2016     Published: April 6, 2016

ABSTRACT

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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