title: iNOS-derived nitric oxide promotes glycolysis by inducing pyruvate kinase M2 nuclear translocation in ovarian cancer.
abstract: 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.
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.|Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research, Guangzhou 510515, China.|Guangzhou Key Laboratory of Tumor Immunology Research, Southern Medical University, Guangzhou 510515, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Li
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
authors.forename: Lingqun
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.|Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research, Guangzhou 510515, China.|Guangzhou Key Laboratory of Tumor Immunology Research, Southern Medical University, Guangzhou 510515, China.
authors.forename: Bingtao
authors.initials: B
authors.lastname: Hao
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Gao
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
authors.forename: Qianli
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
authors.forename: Keyi
authors.initials: K
authors.lastname: Li
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
authors.forename: Mengqiu
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Vascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Zhengjun
authors.initials: Z
authors.lastname: Liu
authors.affiliation: School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.|Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Qiaohong
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Oncology, Henan Provincial People's Hospital, Zhengzhou 450003, Henan, China.
authors.forename: Xiqing
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Oncology, Guangzhou Hospital of Integrated Traditional and Western Medicine, Guangzhou 510800, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Department of Human Anatomy, Southern Medical University, Guangzhou 510515, China.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Huang
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.|Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research, Guangzhou 510515, China.|Guangzhou Key Laboratory of Tumor Immunology Research, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
authors.forename: Kaitai
authors.initials: K
authors.lastname: Yao
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.|Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research, Guangzhou 510515, China.|Guangzhou Key Laboratory of Tumor Immunology Research, Southern Medical University, Guangzhou 510515, China.
authors.forename: Qiuzhen
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000328:Adult; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D005260:Female; D006019:Glycolysis; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport; D013963:Thyroid Hormones / Q000378:metabolism*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C496319:NOS2 protein, human
keywords: EGFR/ERK2; PKM2; Warburg effect; iNOS; nitric oxide