机构：[1]Cancer Research Institute, Southern Medical University, Guangzhou 510515, China[2]Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research, Guangzhou 510515, China[3]Guangzhou Key Laboratory of Tumor Immunology Research, Southern Medical University, Guangzhou 510515, China[4]Department of Vascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China[5]School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China[6]Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA[7]Department of Oncology, Henan Provincial People’s Hospital, Zhengzhou 450003, Henan, China[8]Department of Oncology, Guangzhou Hospital of Integrated Traditional and Western Medicine, Guangzhou 510800, China[9]Department of Human Anatomy, Southern Medical University, Guangzhou 510515, China
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.
基金：
This work was supported by grants from the National Natural Science Foundation of China (No. 81472834; No. 61427807), National Basic Research Program of China (973 Program, No. 2010CB529401), Guangzhou Science and Technology research project (No. 201400000001-1), Ministry of education key laboratory open project (No. 2013jsz105) and the Introduction of Major R&D Projects in Fujian Province (2012I2014).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2016]版：
大类|1 区医学
小类|2 区细胞生物学2 区肿瘤学
最新[2025]版：
无
第一作者：
第一作者机构：[1]Cancer Research Institute, Southern Medical University, Guangzhou 510515, China[2]Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research, Guangzhou 510515, China[3]Guangzhou Key Laboratory of Tumor Immunology Research, Southern Medical University, Guangzhou 510515, China
共同第一作者：
通讯作者：
通讯机构：[1]Cancer Research Institute, Southern Medical University, Guangzhou 510515, China[2]Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research, Guangzhou 510515, China[3]Guangzhou Key Laboratory of Tumor Immunology Research, Southern Medical University, Guangzhou 510515, China
推荐引用方式(GB/T 7714)：
Linlin Li,Lingqun Zhu,Bingtao Hao,et al.iNOS-derived nitric oxide promotes glycolysis by inducing pyruvate kinase M2 nuclear translocation in ovarian cancer.[J].Oncotarget.2017,8(20):33047-33063.doi:10.18632/oncotarget.16523.
医学