Roles of nitric oxide in tumor growth.

Jenkins, D. C.; Charles, IG; Thomsen, Lindy L.; Moss, D. W.; Holmes, Lesley; Baylis, S.A.; Rhodes, Peter; Westmore, K; Emson, P.C.; Moncada, Salvador

doi:10.1073/pnas.92.10.4392

Cited by 706 publications

(490 citation statements)

References 17 publications

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“…NO in low concentrations is known to have benign, modulating, and regulatory effects on normal mammalian and human biology. Higher concentrations of NO have been shown to be both damaging and pathologic to physiologic processes resulting in mutational events which might lead to cancer and promote progression of the tumor [6][7][8]. Our laboratory and others have shown that NO is overexpressed in many human cancers [9].…”

Section: Introductionmentioning

confidence: 79%

Part III. Molecular changes induced by high nitric oxide adaptation in human breast cancer cell line BT-20 (BT-20-HNO): a switch from aerobic to anaerobic metabolism

et al. 2012

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Nutrient deprivation and reactive oxygen species (ROS) play an important role in breast cancer mitochondrial adaptation. Adaptations to these conditions allow cells to survive in the stressful microenvironment of the tumor bed. This study is directed at defining the consequences of High Nitric Oxide (HNO) exposure to mitochondria in human breast cancer cells. The breast cancer cell line BT-20 (parent) was adapted to HNO as previously reported, resulting in the BT-20-HNO cell line. Both cell lines were analyzed by a variety of methods including MTT, LDH leakage assay, DNA sequencing, and Western blot analysis. The LDH assay and the gene chip data showed that BT-20-HNO was more prone to use the glycolytic pathway than the parent cell line. The BT-20-HNO cells were also more resistant to the apoptotic inducing agent salinomycin, which suggests that p53 may be mutated in these cells. Polymerase chain reaction (PCR) followed by DNA sequencing of the p53 gene showed that it was, in fact, mutated at the DNA-binding site (L194F). Western blot analysis showed that p53 was significantly upregulated in these cells. These results suggest that free radicals, such as nitric oxide (NO), pressure human breast tumor cells to acquire an aggressive phenotype and resistance to apoptosis. These data collectively provide a mechanism by which the dysregulation of ROS in the mitochondria of breast cancer cells can result in DNA damage.Keywords Breast cancer . Nitric oxide . p53 . Reactive oxygen species (ROS) . Glycolysis and apoptosis . Aerobic and anaerobic metabolisms

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Section: Introductionmentioning

confidence: 79%

Part III. Molecular changes induced by high nitric oxide adaptation in human breast cancer cell line BT-20 (BT-20-HNO): a switch from aerobic to anaerobic metabolism

et al. 2012

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“…The dual pro-and anti-tumour action of NO was recently demonstrated to be dependent on the local concentration of the molecules (Jenkins et al, 1995). An inverse relationship between the generation of NO and the metastatic potential of a tumour was also proposed (Dong et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…B and D represent the modified Wright's stain of cells as in A and C, respectively (original magnification: A-D, x 400; E, x 200) mutagen (Mordan et al, 1993). The dual pro-and anti-tumour action of NO was recently demonstrated to be dependent on the local concentration of the molecules (Jenkins et al, 1995). An inverse relationship between the generation of NO and the metastatic potential of a tumour was also proposed (Dong et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer

Liu

Wang²,

Chen³

et al. 1998

Br J Cancer

144

111

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Summary Monocyte-macrophage series have an important role in host surveillance against cancer. The cytotoxic/cytostatic activity of macrophages is, to a great extent, attributed to the up-regulation of inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO). Here, in 28 patients with primary lung cancer and 20 control subjects, we measured the concentration of exhaled NO and nitrite in epithelial lining fluid (ELF) using a chemiluminescence NO analyser, and studied NOS expression in alveolar macrophages (AM) and lung tissues by flow cytometry; immunohistochemical analysis was also undertaken. The mean fluorescence intensity (Fl) of iNOS expression in AM was significantly increased in patients with lung cancer (tumour side 263.5 ± 15.2 Fl, normal side 232.4 ± 18.6 Fl; n = 28) compared with that in control subjects (27.3 ± 3.2 Fl; n = 20, P< 0.001). The level of exhaled NO from cancer patients (16.9 ± 0.9 p.p.b.; n = 28) was significantly higher than that in the control group (6.0 ± 0.5 p.p.b.; n = 20, P < 0.001). The level of nitrite was also significantly higher in ELF from cancer patients (tumour side 271.1 ± 28.9 nm and normal side 257.4 ± 19.6 nm vs control subjects 32.9 + 4.1 nM; P< 0.001). The intensity of iNOS expression in AM was correlated with the level of exhaled NO (rS = 0.73, n = 76, P < 0.001) and the nitrite released in ELF (r, = 0.56, n = 76, P < 0.001). The nitrite generation of cultured AM from patients with lung cancer was significantly enhanced compared with that of control subjects after culture for 24 h (tumour side 5.75 ± 0.69 and normal side 5.68 ± 0.58 gM per 106 cells vs control group 38.3 + 3.6 nm per 106 cells; P< 0.001). The distribution of iNOS was identified in AM, tumour-associated macrophages, endothelium, chondrocytes, airway epithelium of both lungs and malignant cells (adenocarcinoma and alveolar cell carcinoma) of cancer patients. cNOS was labelled in alveolar macrophages, endothelial cells and nerve elements from lung tissue. Our results indicate that, in patients with primary lung cancer, the production of NO from alveolar macrophages was increased as a result of the up-regulation of iNOS activity. The increased NO production was not specific to the tumour side and might be attributed to the tumour-associated non-specific immunological and inflammatory processes of the host.Keywords: lung cancer; alveolar macrophage; nitric oxide; nitric oxide synthase; nitrite; cytotoxicity The host defence mechanism is important in the development and growth of tumours. The incidence of malignancy is reported to be increased in subjects with compromised immunity (Penn, 1986). The complex defence and immunological mechanisms against cancer contain several types of cells, including macrophages (Fidler et al, 1988) and mediators, such as nitric oxide (NO) (Farias-Eisner et al, 1996).Macrophages have a role in host surveillance against cancer (Hibbs et al, 1978). Macrophages can be activated both in vivo and in vitro to kill tumour cells. The oncolytic activity of macrophag...

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“…While NO had been shown to have anti-tumour p roperties [10], Jenkins et al [42][1995] first reporte d the surprising finding that human carcinoma cells transfected with a murine iNOS cDNA cassette (DL D-1 cells generating 20 pmol min-1 mg-1 NOS activ ity) showed increased tumour growth, rather than d ecreased growth. Using a nude mouse/xanograft mo del it was shown that growth of these NO-generatin g tumours was accompanied by increased neovascul arization.…”

Section: No and Tumour Cell Angiogenesismentioning

confidence: 99%

The role of nitric oxide in cancer

Liu

Loizidou³

et al. 2002

Cell Res

694

500

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Nitric oxide (NO) is a pleiotropic regulator, critical to numerous biological processes, including vasodilatation, neurotransmission and macrophage-mediated immunity. The family of nitric oxide synthases (NOS) comprises inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS). Interestingly, various studies have shown that all three isoforms can be involved in promoting or inhibiting the etiology of cancer. NOS activity has been detected in tumour cells of various histogenetic origins and has been associated with tumour grade, proliferation rate and expression of important signaling components associated with cancer development such as the oestrogen receptor. It appears that high levels of NOS expression (for example, generated by activated macrophages) may be cytostatic or cytotoxic for tumor cells, whereas low level activity can have the opposite effect and promote tumour growth. Paradoxically therefore, NO (and related reactive nitrogen species) may have both genotoxic and angiogenic properties. Increased NO-generation in a cell may select mutant p53 cells and contribute to tumour angiogenesis by upregulating VEGF. In addition, NO may modulate tumour DNA repair mechanisms by upregulating p53, poly(ADP-ribose) polymerase (PARP) and the DNA-dependent protein kinase (DNA-PK). An understanding at the molecular level of the role of NO in cancer will have profound therapeutic implications for the diagnosis and treatment of disease.

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Roles of nitric oxide in tumor growth.

Abstract: A subclone of the human colon adenocarci-

Cited by 706 publications

References 17 publications

Part III. Molecular changes induced by high nitric oxide adaptation in human breast cancer cell line BT-20 (BT-20-HNO): a switch from aerobic to anaerobic metabolism

Part III. Molecular changes induced by high nitric oxide adaptation in human breast cancer cell line BT-20 (BT-20-HNO): a switch from aerobic to anaerobic metabolism

Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer

The role of nitric oxide in cancer

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