Inactivation of ribonucleotide reductase by nitric oxide

Lepoivre, Michel; Fieschi, Franck; Covès, Jacques; Thelander, Lars; Fontecave, Marc

doi:10.1016/0006-291x(91)91390-x

Cited by 313 publications

(174 citation statements)

References 13 publications

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“…The nitric oxide synthase (NOS) family of enzymes generate NO, and many of its functions are mediated by its binding to Fe in heme and nonheme Fe-containing proteins (4)(5)(6)(7)(8)(9)(10).…”

Section: Nitrogen Monoxide (No)-mediated Iron Release From Cells Is Lmentioning

confidence: 99%

“…NO cytotoxicity is partly caused by its interaction with the Fe-containing rate-limiting enzyme of DNA synthesis, ribonucleotide reductase (6), and [Fe-S] cluster enzymes, e.g., mitochondrial aconitase (8,9). Tumor cells cocultured with M s exhibit decreased DNA synthesis and a pronounced loss of Fe (1,2).…”

Section: Nitrogen Monoxide (No)-mediated Iron Release From Cells Is Lmentioning

confidence: 99%

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Nitrogen monoxide (NO)-mediated iron release from cells is linked to NO-induced glutathione efflux via multidrug resistance-associated protein 1

Watts

Hawkins

Ponka

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

116

119

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Nitrogen monoxide (NO) plays a role in the cytotoxic mechanisms of activated macrophages against tumor cells by inducing iron (Fe) release. We have shown that NO-mediated Fe efflux from cells required glutathione (GSH), and we have hypothesized that a GS–Fe–NO complex was released. Hence, we studied the role of the GSH-conjugate transporter multidrug resistance-associated protein 1 (MRP1) in NO-mediated Fe efflux. MCF7-VP cells overexpressing MRP1 exhibited a 3- to 4-fold increase in NO-mediated 59 Fe and GSH efflux compared with WT cells (MCF7-WT) over 4 h. Similar results were found for other MRP1-overexpressing cell types but not those expressing another drug efflux pump, P-glycoprotein. NO-mediated 59 Fe and GSH efflux were temperature- and energy-dependent and were significantly decreased by the GSH-depleting agent and MRP1 transport inhibitor l -buthionine-[ S , R ]-sulfoximine. Other MRP1 inhibitors, MK571, probenecid, and difloxacin, significantly inhibited NO-mediated 59 Fe release. EPR spectroscopy demonstrated the dinitrosyl-dithiol-Fe complex (DNIC) peak in NO-treated cells was increased by MRP1 inhibitors, indicating inhibited DNIC transport from cells. The extent of DNIC accumulation correlated with the ability of MRP1 inhibitors to prevent NO-mediated 59 Fe efflux. MCF7-VP cells were more sensitive than MCF7-WT cells to growth inhibition by effects of NO, which was potentiated by l -buthionine-[ S , R ]-sulfoximine. These data indicate the importance of GSH in NO-mediated inhibition of proliferation. Collectively, NO stimulates Fe and GSH efflux from cells via MRP1. Active transport of NO by MRP1 overcomes diffusion that is inefficient and nontargeted, which has broad ramifications for understanding NO biology.

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Section: Nitrogen Monoxide (No)-mediated Iron Release From Cells Is Lmentioning

confidence: 99%

Section: Nitrogen Monoxide (No)-mediated Iron Release From Cells Is Lmentioning

confidence: 99%

Nitrogen monoxide (NO)-mediated iron release from cells is linked to NO-induced glutathione efflux via multidrug resistance-associated protein 1

Watts

Hawkins

Ponka

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

116

119

View full text Add to dashboard Cite

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“…In our model two systems seem to dominate: the ¬_arginine-NO pathway and the RAS. NO as an antiproliferative factor, can inhibit ribonucleotide reductase (Lepoivre et al 1991), a rate-limiting enzyme in deoxyribonucleotide synthesis. Moreover, the activity of thymidine kinase, necessary for DNA synthesis, is inhibited by the NO donor S-nitroso-N-acetylpenicillamine (Garg & Hassid, 1993).…”

Section: Discussionmentioning

confidence: 99%

Effect of Captopril in L‐Name‐Induced Hypertension on the Rat Myocardium, Aorta, Brain and Kidney

Bernátová

Pecháňová

Šimko

1999

Experimental Physiology

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summary Long-term administration of N G -nitro-¬_arginine methyl ester (¬_NAME) induces development of hypertension and hypertrophy of the left ventricle in rats. The aim of the present study was to demonstrate the effect of chronic ¬_NAME treatment on DNA and RNA concentration, and protein synthesis in the rat heart, aorta, brain and kidney and to determine the effect of angiotensin converting enzyme (ACE) inhibitor captopril on these potential alterations. Four groups of rats were investigated: control, ¬_NAME (40 mg kg¢ day¢), captopril (100 mg kg¢ day¢), and ¬_NAME (40 mg kg¢ day¢) + captopril (100 mg kg¢ day¢). NO synthase activity in the heart, aorta, brain and kidney was found to be decreased in the ¬_NAME group. In the group of rats treated with ¬_NAME + captopril, captopril did not affect NO synthase inhibition. Captopril, however, completely prevented development of hypertension and left ventricular hypertrophy in this group. In the ¬_NAME group, DNA and RNA concentrations, as well as [14 C]leucine incorporation, were significantly increased in all the tissues investigated. In the ¬_NAME + captopril group, captopril completely prevented the enhancement of DNA and RNA concentrations and [ 14 C]leucine incorporation in all tissues compared to the ¬_NAME group. Moreover, a significant decrease in RNA concentration and [ 14 C]leucine incorporation below control values was found in the captopril group as well as the ¬_NAME + captopril group in all the tissues investigated. We conclude that captopril prevented the development of hypertension and increase in nucleic acid concentration and protein synthesis in the heart, aorta, brain and kidney in rats treated with ¬_NAME + captopril. However, this protective effect of captopril was not associated with increased NO synthase activity in this model of hypertension.

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“…It has been reported that NO affects immune cells by damaging genomic DNA, mitochondrial respiratory chain and ribonucleotide reductase activity. [67][68][69][70] In addition, it has been reported that peroxynitrite, the products of NO, can inhibit T lymphocyte activation and proliferation by impairing tyrosine phosphorylation. 71 Both tyrosine nitration and protein carbonylation can exert strong effects on immune cells.…”

Section: Discussionmentioning

confidence: 99%

p53 regulates mesenchymal stem cell-mediated tumor suppression in a tumor microenvironment through immune modulation

Huang

et al. 2013

Oncogene

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p53 is one of the most studied genes in cancer biology, and mutations in this gene may be predictive for the development of many types of cancer in humans and in animals. However, whether p53 mutations in non-tumor stromal cells can affect tumor development has received very little attention. In this study, we show that B16F0 melanoma cells form much larger tumors in p53-deficient mice than in wild-type mice, indicating a potential role of p53 deficiency in non-tumor cells of the microenvironment. As mesenchymal stem cells (MSCs) are attracted to tumors and form a major component of the tumor microenvironment, we examined the potential role of p53 status in MSCs in tumor development. We found that larger tumors resulted when B16F0 melanoma cells were co-injected with bone marrow MSCs derived from p53-deficient mice rather than MSCs from wild-type mice. Interestingly, this tumor-promoting effect by p53-deficient MSCs was not observed in non-obese diabetic/severe combined immunodeficiency mice, indicating the immune response has a critical role. Indeed, in the presence of inflammatory cytokines, p53-deficient MSCs expressed more inducible nitric oxide synthase (iNOS) and exhibited greater immunosuppressive capacity. Importantly, tumor promotion by p53-deficient MSCs was abolished by administration of S-methylisothiourea, an iNOS inhibitor. Therefore, our data demonstrate that p53 status in tumor stromal cells has a key role in tumor development by modulating immune responses.

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Inactivation of ribonucleotide reductase by nitric oxide

Cited by 313 publications

References 13 publications

Nitrogen monoxide (NO)-mediated iron release from cells is linked to NO-induced glutathione efflux via multidrug resistance-associated protein 1

Nitrogen monoxide (NO)-mediated iron release from cells is linked to NO-induced glutathione efflux via multidrug resistance-associated protein 1

Effect of Captopril in L‐Name‐Induced Hypertension on the Rat Myocardium, Aorta, Brain and Kidney

p53 regulates mesenchymal stem cell-mediated tumor suppression in a tumor microenvironment through immune modulation

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