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.

Nitric Oxide as a Potential Adjuvant Therapeutic for Neuroblastoma: Effects of NO on Murine N2a Cells

“…The ability of high levels of NO to reduce colony formation has been previously observed [41]. Although the underlying molecular mechanisms for this effect are still being elucidated, it is known that excess NO impedes epidermal growth factor receptor/extracellular signal regulated kinase 2 (EGFR/ERK2)-dependent nuclear translocation of pyruvate kinase M2 (PKM2), thereby inhibiting glycolysis and inducing cell death [41,42]. It is also known that various NO-donor treated malignancies and macrophages have shown increased p53 expression, which led to apoptosis [35,36].…”

“…These experiments showed that after 24 h of exposure to GSNO, 21-24% of cells were no longer metabolically active and 100% were incapable of colony formation. The ability of high levels of NO to reduce colony formation has been previously observed [41]. Although the underlying molecular mechanisms for this effect are still being elucidated, it is known that excess NO impedes epidermal growth factor receptor/extracellular signal regulated kinase 2 (EGFR/ERK2)-dependent nuclear translocation of pyruvate kinase M2 (PKM2), thereby inhibiting glycolysis and inducing cell death [41,42].…”

The Glycolytic Switch in Tumors: How Many Players Are Involved?

“…Carboxyl terminus of Hsc70-interacting protein (CHIP), an E3 ligase, inhibits aerobic glycolysis progression of ovarian carcinomas through CHIP-mediated PKM2 degradation 142 . iNOS/NO promotes glycolysis via inducing PKM2 nuclear translocation 143 . Mitochondrial calcium uptake 1 (MICU1) increases aerobic glycolysis and chemoresistance in ovarian cancer 144 .…”

Differential research of inflammatory and related mediators in BPH, histological prostatitis and PCa

“…In ovarian cancer cells, the researchers found that NO has dual biological functions in tumour cells, and low concentration of NO promoted the glycolysis while inhibits the glycolysis at high concentrations. The iNOS induced by LPS can enhance the glycolysis in ovarian cancer cells, and the levels of iNOS mRNA can predict the poor prognosis in the patients of ovarian cancer (Li et al., ). Therefore, NO was quite complex in tumour cells, and NOS/NO has a dual role in carcinogenesis, progression and treatment by NO concentration and exposure time dependence, NOS isomers and tumour microenvironment and other factors (Lala & Chakraborty, ).…”