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

Jiangjiang Li; Ya He; Zheqiong Tan; Jingchen Lu; Liling Li; Xin Song; Feng Shi; Longlong Xie; Shuo You; Xiangjian Luo; Namei Li; Yueshuo Li; Xiaolan Liu; Min Tang; Xinxian Weng; Wei Yi; Jia Fan; Jian Zhou; Gao Qiang; ShuangJian Qiu; Weizhong Wu; Ann M Bode; Ya Cao

doi:10.7150/thno.21524

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

Theranostics. 2018 Jul 16;8(15):4050-4061. doi: 10.7150/thno.21524. eCollection 2018.

Authors

Jiangjiang Li^{1

2

3

4}, Ya He^{1

2

3}, Zheqiong Tan^{1

2

3}, Jingchen Lu^{1

2

3}, Liling Li^{1

2

3}, Xin Song⁵, Feng Shi^{1

2

3}, Longlong Xie^{1

2

3}, Shuo You⁶, Xiangjian Luo^{1

2

3}, Namei Li^{1

2

3}, Yueshuo Li^{1

2

3}, Xiaolan Liu^{1

2

3}, Min Tang^{1

2

3}, Xinxian Weng^{1

2

3}, Wei Yi^{1

2

3}, Jia Fan⁷, Jian Zhou⁷, Gao Qiang⁷, ShuangJian Qiu⁷, Weizhong Wu⁷, Ann M Bode⁸, Ya Cao^{1

2

3

4

9}

Affiliations

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.

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: HIF1-α; Warburg effect; isocitrate dehydrogenase 2; lung cancer; tumor growth.

MeSH terms

A549 Cells
Animals
Cell Proliferation*
Disease Models, Animal
Heterografts
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Immunohistochemistry
Isocitrate Dehydrogenase / metabolism*
Lung Neoplasms / pathology*
Lung Neoplasms / physiopathology*
Mice
Microscopy
Models, Theoretical
Neoplasm Transplantation

Substances

HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
IDH2 protein, human
Isocitrate Dehydrogenase