Nitric Oxide, a Mediator of Inflammation, Suppresses Tumorigenesis

Hussain, S. Perwez; Trivers, Glennwood E.; Hofseth, Lorne J.; He, Peijun; Shaikh, Irfan Ahmed; Mechanic, Leah E.; Doja, Saira; Jiang, Weidong; Subleski, Jeffrey; Shorts, Lynnette; Haines, Diana C.; Laubach, Victor E.; Wiltrout, Robert H.; Djurickovic, Draginja; Harris, Curtis C.

doi:10.1158/0008-5472.can-04-2201

Cited by 119 publications

(75 citation statements)

References 34 publications

(27 reference statements)

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“…NO is known to be involved in diverse processes in numerous physiological and pathophysiological conditions; previous studies have suggested that NO can exert a negative effect on the (10,(12)(13)(14)(15)(16)(17)(18). However, studies concerning the effects of NO on HCC cells are rare.…”

Section: Discussionmentioning

confidence: 99%

Effects of nitric oxide on the biological behavior of HepG2 human hepatocellular carcinoma cells

Zhou

Zhang

2016

Experimental and Therapeutic Medicine

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Abstract. Many studies have found the function of nitric oxide (NO) in cancer as a pro-neoplastic vs. an anti-neoplastic effector, but the role of NO in hepatocellular carcinoma (HCC) remains unclear. The present study aimed to investigate the effects of nitric oxide (NO) on the biological behavior of the human hepatocellular carcinoma cell line HepG2. HepG2 cell was cultured in vitro and treated with or without sodium nitroprusside (SNP), a NO donor. Subsequently, we evaluated the effects of NO in cell proliferation, cell cycle, apoptosis, migration and invasion by MTT assay, flow cytometry, wound healing assay and Matrigel invasion assay. We demonstrate that NO significantly inhibited HepG2 cell proliferation by inducing G 0 /G 1 phase arrest in a dose-dependent manner. In addition, compared to the control group, cells treated with SNP showed obviously higher apoptosis ratios in a dose-dependent manner. Furthermore, we revealed that NO effectively inhibited the ability of migration and invasion of HepG2 cells. Taken together, our results suggested that NO has an important role in the regulation of biological behavior in HepG2 cells and the potential for use in the prevention and treatment of HCC.

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Section: Discussionmentioning

confidence: 99%

Effects of nitric oxide on the biological behavior of HepG2 human hepatocellular carcinoma cells

Zhou

Zhang

2016

Experimental and Therapeutic Medicine

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“…Macrophage-derived NO is essential for the suppression of some tumors (54). Recent studies have shown that there is a higher incidence of lymphomas in p53/NOS-2 double knockout mice (55). Yet there was a significant delay in the onset of tumors in p53 Ϫ/Ϫ mice that were fed TEMPOL, an SOD mimetic (56).…”

Section: Discussionmentioning

confidence: 99%

Superoxide Fluxes Limit Nitric Oxide-induced Signaling

Thomas

Ridnour

Espey

et al. 2006

Journal of Biological Chemistry

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105

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Independently, superoxide (O 2 ؊) and nitric oxide (NO) are biologically important signaling molecules. When co-generated, these radicals react rapidly to form powerful oxidizing and nitrating intermediates. Although this reaction was once thought to be solely cytotoxic, herein we demonstrate using MCF7, macrophage, and endothelial cells that when nanomolar levels of NO and O 2 ؊ were produced concomitantly, the effective NO concentration was established by the relative fluxes of these two radicals. Differential regulation of sGC, pERK, HIF-1␣, and p53 were used as biological dosimeters for NO concentration. Introduction of intracellular-or extracellular-generated O 2 ؊ during NO generation resulted in a concomitant increase in oxidative intermediates with a decrease in steady-state NO concentrations and a proportional reduction in the levels of sGC, ERK, HIF-1␣, and p53 regulation. NO responses were restored by addition of SOD. The intermediates formed from the reactions of NO with O 2 ؊ were non-toxic, did not form 3-nitrotyrosine, nor did they elicit any signal transduction responses. H 2 O 2 in bolus or generated from the dismutation of O 2 ؊ by SOD, was cytotoxic at high concentrations and activated p53 independent of NO. This effect was completely inhibited by catalase, suppressed by NO, and exacerbated by intracellular catalase inhibition. We conclude that the reaction of O 2 ؊ with NO is an important regulatory mechanism, which modulates signaling pathways by limiting steady-state levels of NO and preventing H 2 O 2 formation from O 2 ؊ .

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“…NO ⅐ has potent anti-tumor and anti-atherosclerotic effects that are closely associated with its ability to block cell proliferation (17,20). This activity of NO ⅐ has been ascribed to both cGMP-dependent and -independent mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Nitric oxide (NO ⅐ ) regulates a wide range of cellular activities including gene expression (12)(13)(14)(15)(16), cell proliferation (17,18), and apoptosis (19) that are closely linked to its anti-tumor and anti-atherosclerotic properties (17,20). Using a microarraybased approach in soluble guanylate cyclase-deficient cells, we recently demonstrated that NO ⅐ predominately regulated a large set of cell cycle genes independent cGMP (15).…”

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confidence: 99%

Nitric Oxide Down-regulates Polo-like Kinase 1 through a Proximal Promoter Cell Cycle Gene Homology Region

Zhang

Wang

Kern

et al. 2007

Journal of Biological Chemistry

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Polo-like kinase 1 (PLK1) is an evolutionarily conserved serine/threonine kinase essential for cell mitosis. As a master cell cycle regulator, p21/Waf1 plays a critical role in cell cycle progression. Nitric oxide (NO ⅐ ) has been shown to down-regulate PLK1 and up-regulate p21/Waf1 independent of cGMP. Here, the respective roles of p38 MAPK and p21/Waf1 in NO ⅐ -mediated PLK1 repression were investigated using differentiated U937 cells that lack soluble guanylate cyclase. NO ⅐ was shown to down-regulate both PLK1 mRNA and protein. Nuclear run-on assays and mRNA stability studies demonstrated that the effect of NO ⅐ on PLK1 expression was associated with decreased transcription without changes in transcript stability. SB202190, a p38 MAPK inhibitor, prevented transcriptional repression of PLK1 by NO ⅐ . Transfection with dominant-negative p38 MAPK mutant eliminated the NO ⅐ effect on both p21/Waf1 and PLK1 gene expression. Knockdown of p21/Waf1 with siRNA also substantially reduced the regulatory effect of NO ⅐ on PLK1. Reporter gene experiments showed that NO ⅐ decreased activity of the PLK1 proximal promoter, an effect that was blocked by p38 MAPK inhibitor. Deletion or mutation of the CDE/CHR promoter site, an element regulated by p21/Waf1, increased base-line promoter activity and abolished NO ⅐ repression of the PLK1 promoter. Likewise, electrophoretic mobility shift assays with CDE/CHR probe revealed a NO ⅐ -mediated change in protein-probe complex formation. Competition with various unlabeled CDE/CHR mutant sequences showed that NO ⅐ increased nuclear protein binding to intact CHR. These results demonstrate that a NO ⅐ -p38 MAPK-p21/Waf1 signal transduction pathway represses PLK1 through a canonical CDE/CHR promoter element.

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Nitric Oxide, a Mediator of Inflammation, Suppresses Tumorigenesis

Cited by 119 publications

References 34 publications

Effects of nitric oxide on the biological behavior of HepG2 human hepatocellular carcinoma cells

Effects of nitric oxide on the biological behavior of HepG2 human hepatocellular carcinoma cells

Superoxide Fluxes Limit Nitric Oxide-induced Signaling

Nitric Oxide Down-regulates Polo-like Kinase 1 through a Proximal Promoter Cell Cycle Gene Homology Region

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