Theranostics 2018; 8(15):4050-4061. doi:10.7150/thno.21524 This issue

Research Paper

Wild-type IDH2 promotes the Warburg effect and tumor growth through HIF1α in lung cancer

Jiangjiang Li1,2,3,4, Ya He1,2,3, Zheqiong Tan1,2,3, Jingchen Lu1,2,3, Liling Li1,2,3, Xin Song5, Feng Shi1,2,3, Longlong Xie1,2,3, Shuo You6, Xiangjian Luo1,2,3, Namei Li1,2,3, Yueshuo Li1,2,3, Xiaolan Liu1,2,3, Min Tang1,2,3, Xinxian Weng1,2,3, Wei Yi1,2,3, Jia Fan7, Jian Zhou7, Gao Qiang7, ShuangJian Qiu7, Weizhong Wu7, Ann M. Bode8, Ya Cao1,2,3,4,9✉

1. Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, China
2. Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha 410078, China
3. Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha 410078, China
4. Research Center for Technologies of Nucleic Acid-Based Diagnostics and Therapeutics Hunan Province, Changsha 410078, China
5. Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming 650118, China
6. Second Affiliated Hospital of Xiangya, Central South University, Changsha 410000, China
7. Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai 200000, China
8. The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
9. National Joint Engineering Research Center for Genetic Diagnostics of Infectious Diseases and Cancer, Changsha 410078, China

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Li J, He Y, Tan Z, Lu J, Li L, Song X, Shi F, Xie L, You S, Luo X, Li N, Li Y, Liu X, Tang M, Weng X, Yi W, Fan J, Zhou J, Qiang G, Qiu S, Wu W, Bode AM, Cao Y. Wild-type IDH2 promotes the Warburg effect and tumor growth through HIF1α in lung cancer. Theranostics 2018; 8(15):4050-4061. doi:10.7150/thno.21524. Available from https://www.thno.org/v08p4050.htm

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Abstract

Graphic abstract

Hotspot mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) have been studied in several cancers. However, the function of wild-type IDH2 in lung cancer and the mechanism of its contribution to growth of cancer cells remain unknown. Here, we explored the role and mechanism of wild-type IDH2 in promoting growth of lung cancer.

Methods: Information regarding genomic and clinical application focusing on IDH2 in cancer was examined in several databases of more than 1,000 tumor samples. IDH2 expression was assessed by immunohistochemistry in tissues from lung cancer patients. The biological functions of IDH2 were evaluated by using cell-based assays and in vivo xenograft mouse models.

Results: Here we reported that wild-type IDH2 is up-regulated and is an indicator of poor survival in lung cancer and several other cancers. Targeting IDH2 with shRNA resulted in decreased HIF1α expression, leading to the attenuation of lung cancer cell proliferation and tumor growth. Treatment of lung cancer cells with AGI-6780 (a small molecule inhibitor of IDH2), PX-478 (an inhibitor of HIF1α) or incubation with octyl-α-KG inhibited lung cancer cell proliferation.

Conclusion: IDH2 promotes the Warburg effect and lung cancer cell growth, which is mediated through HIF1α activation followed by decreased α-KG. Therefore, IDH2 could possibly serve as a novel therapeutic target for lung cancer.

Keywords: isocitrate dehydrogenase 2, lung cancer, Warburg effect, tumor growth, HIF1-α