Research Papers:

iNOS-derived nitric oxide promotes glycolysis by inducing pyruvate kinase M2 nuclear translocation in ovarian cancer

Linlin Li, Lingqun Zhu, Bingtao Hao, Wenwen Gao, Qianli Wang, Keyi Li, Meng Wang, Mengqiu Huang, Zhengjun Liu, Qiaohong Yang, Xiqing Li, Zhuo Zhong, Wenhua Huang, Guanghui Xiao, Yang Xu, Kaitai Yao and Qiuzhen Liu _

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Oncotarget. 2017; 8:33047-33063. https://doi.org/10.18632/oncotarget.16523

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Linlin Li1,2,3,*, Lingqun Zhu1,*, Bingtao Hao1,2,3, Wenwen Gao1, Qianli Wang1, Keyi Li1, Meng Wang1, Mengqiu Huang1, Zhengjun Liu4, Qiaohong Yang5,6, Xiqing Li7, Zhuo Zhong8, Wenhua Huang9, Guanghui Xiao1, Yang Xu1,2,3, Kaitai Yao1, Qiuzhen Liu1,2,3

1Cancer Research Institute, Southern Medical University, Guangzhou 510515, China

2Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research, Guangzhou 510515, China

3Guangzhou Key Laboratory of Tumor Immunology Research, Southern Medical University, Guangzhou 510515, China

4Department of Vascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

5School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China

6Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA

7Department of Oncology, Henan Provincial People’s Hospital, Zhengzhou 450003, Henan, China

8Department of Oncology, Guangzhou Hospital of Integrated Traditional and Western Medicine, Guangzhou 510800, China

9Department of Human Anatomy, Southern Medical University, Guangzhou 510515, China

*These authors have contributed equally to this work

Correspondence to:

Qiuzhen Liu, email: [email protected]

Kaitai Yao, email: [email protected]

Keywords: nitric oxide, iNOS, Warburg effect, PKM2, EGFR/ERK2

Received: October 19, 2016     Accepted: March 15, 2017     Published: March 23, 2017


Aerobic glycolysis is essential for tumor growth and survival. Activation of multiple carcinogenic signals contributes to metabolism reprogramming during malignant transformation of cancer. Recently nitric oxide has been noted to promote glycolysis but the mechanism remains elusive. We report here the dual role of nitric oxide in glycolysis: low/physiological nitric oxide (≤ 100 nM) promotes glycolysis for ATP production, oxidative defense and cell proliferation of ovary cancer cells, whereas excess nitric oxide (≥ 500 nM) inhibits it. Nitric oxide has a positive effect on glycolysis by inducing PKM2 nuclear translocation in an EGFR/ERK2 signaling-dependent manner. Moreover, iNOS induced by mild inflammatory stimulation increased glycolysis and cell proliferation by producing low doses of nitric oxide, while hyper inflammation induced iNOS inhibited it by producing excess nitric oxide. Finally, iNOS expression is abnormally increased in ovarian cancer tissues and is correlated with PKM2 expression. Overexpression of iNOS is associated with aggressive phenotype and poor survival outcome in ovarian cancer patients. Our study indicated that iNOS/NO play a dual role of in tumor glycolysis and progression, and established a bridge between iNOS/NO signaling pathway and EGFR/ERK2/PKM2 signaling pathway, suggesting that interfering glycolysis by targeting the iNOS/NO/PKM2 axis may be a valuable new therapeutic approach of treating ovarian cancer.

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