iNOS-derived nitric oxide promotes glycolysis by inducing pyruvate kinase M2 nuclear translocation in ovarian cancer.
iNOS-derived nitric oxide promotes glycolysis by inducing pyruvate kinase M2 nuclear translocation in ovarian cancer.
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DOI：
10.18632/oncotarget.16523
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发表时间：
2017-05-16
期刊：
影响因子：
--
通讯作者：
Liu Q
中科院分区：
文献类型：
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作者：
Li L;Zhu L;Hao B;Gao W;Wang Q;Li K;Wang M;Huang M;Liu Z;Yang Q;Li X;Zhong Z;Huang W;Xiao G;Xu Y;Yao K;Liu Q
有氧糖酵解对肿瘤生长和存活至关重要。多种致癌信号的激活有助于癌症恶变过程中的代谢重编程。最近，一氧化氮已注意到促进糖酵解，但其机制仍然难以捉摸。我们在此报道了一氧化氮在糖酵解中的双重作用：低/生理性一氧化氮（≤ 100 nM）促进糖酵解以产生ATP、氧化防御和卵巢癌细胞的细胞增殖，而过量的一氧化氮（≥ 500 nM）抑制糖酵解。一氧化氮通过以EGFR/ERK 2信号依赖的方式诱导PKM 2核转位对糖酵解具有积极作用。此外，轻度炎症刺激诱导的iNOS通过产生低剂量的一氧化氮来增加糖酵解和细胞增殖，而过度炎症诱导的iNOS通过产生过量的一氧化氮来抑制糖酵解和细胞增殖。最后，卵巢癌组织中iNOS表达异常增加，并与PKM 2表达相关。iNOS过表达与卵巢癌患者侵袭性表型和不良生存结局相关。我们的研究表明，iNOS/NO在肿瘤糖酵解和肿瘤进展中发挥双重作用，并在iNOS/NO信号通路和EGFR/ERK 2/PKM 2信号通路之间建立了桥梁，提示以iNOS/NO/PKM 2轴为靶点干预糖酵解可能成为卵巢癌治疗的一种有价值的新途径。
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.