Nitric Oxide Regulates Mitochondrial Fatty Acid Metabolism Through Reversible Protein
            <i>S</i>
            -Nitrosylation

Doulias, Paschalis‐Thomas; Τενοπούλου, Μαργαρίτα; Greene, Jennifer L.; Raju, Karthik; Ischiropoulos, Harry

doi:10.1126/scisignal.2003252

Cited by 230 publications

(239 citation statements)

References 35 publications

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“…Interestingly, our data suggest that O-ASCs promoted glycolysis in cancer cells by elevating NO synthesis, which has been shown to have inhibitory effects on enzymes involved in mitochondrial respiration. Previous studies showed that NO affects glycolysis through s-nitrosylation of hexokinase (37). Hexokinase converts glucose to glucose-6-phosphate in the first step of glycolysis and is highly expressed in cancer cells (38).…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

et al. 2015

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Omental adipose stromal cells (O-ASC) are a multipotent population of mesenchymal stem cells contained in the omentum tissue that promote endometrial and ovarian tumor proliferation, migration, and drug resistance. The mechanistic underpinnings of O-ASCs' role in tumor progression and growth are unclear. Here, we propose a novel nitric oxide (NO)-mediated metabolic coupling between O-ASCs and gynecologic cancer cells in which O-ASCs support NO homeostasis in malignant cells. NO is synthesized endogenously by the conversion of L-arginine into citrulline through nitric oxide synthase (NOS). Through arginine depletion in the media using L-arginase and NOS inhibition in cancer cells using N G -nitro-L-arginine methyl ester (L-NAME), we demonstrate that patientderived O-ASCs increase NO levels in ovarian and endometrial cancer cells and promote proliferation in these cells. O-ASCs and cancer cell cocultures revealed that cancer cells use O-ASCsecreted arginine and in turn secrete citrulline in the microenvironment. Interestingly, citrulline increased adipogenesis potential of the O-ASCs. Furthermore, we found that O-ASCs increased NO synthesis in cancer cells, leading to decrease in mitochondrial respiration in these cells. Our findings suggest that O-ASCs upregulate glycolysis and reduce oxidative stress in cancer cells by increasing NO levels through paracrine metabolite secretion. Significantly, we found that O-ASCmediated chemoresistance in cancer cells can be deregulated by altering NO homeostasis. A combined approach of targeting secreted arginine through L-arginase, along with targeting microenvironment-secreted factors using L-NAME, may be a viable therapeutic approach for targeting ovarian and endometrial cancers. Cancer Res; 75(2); 456-71. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

et al. 2015

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“…Ischiropoulos and colleagues further utilized this phenylmercury-based SNO-capture approach to identify up to 1,000 S-nitrosylation sites on hundreds of proteins in various mouse tissues (64,65). The number of S-nitrosylation sites in vivo to nitric oxide were found to be substantially dependent on endothelial nitric oxide synthase (eNOS) or neuronal nitric oxide synthase (nNOS) (64,65).…”

Section: The Expanding Landscape Of the Thiol Redox Proteomementioning

confidence: 99%

The Expanding Landscape of the Thiol Redox Proteome

Yang

Carroll

Liebler

2016

Molecular & Cellular Proteomics

184

111

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Cysteine occupies a unique place in protein chemistry. The nucleophilic thiol group allows cysteine to undergo a broad range of redox modifications beyond classical thiol-disulfide redox equilibria, including S-sulfenylation (-SOH), S-sulfinylation (-SO 2 H), S-sulfonylation (-SO 3 H), S-nitrosylation (-SNO), S-sulfhydration (-SSH), S-glutathionylation (-SSG), and others. Emerging evidence suggests that these post-translational modifications (PTM) are important in cellular redox regulation and protection against oxidative damage. Identification of protein targets of thiol redox modifications is crucial to understanding their roles in biology and disease. However, analysis of these highly labile and dynamic modifications poses challenges. Recent advances in the design of probes for thiol redox forms, together with innovative mass spectrometry based chemoproteomics methods make it possible to perform global, site-specific, and quantitative analyses of thiol redox modifications in complex proteomes.

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“…FAS became more active following S-nitrosylation, indicating that S-nitrosylation plays an important role in adipogenesis. It has been reported that NO regulates mitochondrial fatty acid metabolism through protein S-nitrosylation regulation ( 40 ). Following a MS-based proteomics study, very long chain acyl-CoA dehydrogenase was proposed as a candidate S-nitrosylated protein involved in fatty acid HEK293 cells were transfected with FLAG-tagged FAS-WT or its cysteine mutants (C161A, C1127A, C1471A, and C2091A) and exposed to SNOC or old SNOC.…”

Section: Discussionmentioning

confidence: 99%

“…3B ). , and Cys 2091 have been predicted as candidate sites for FAS S-nitrosylation by a MS-based proteomics study ( 40 ). Thus, we examined whether these three cysteines might be involved in FAS S-nitrosylation.…”

Section: Dimerization and Activation Of Fas Are Mediated By Nomentioning

confidence: 99%

S-nitrosylation of fatty acid synthase regulates its activity through dimerization

Choi

Jung

Kim

et al. 2016

Journal of Lipid Research

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reported that FAS is involved in the regulation of adipose tissue mass ( 1, 10-18 ), a key enzyme regulating energy metabolism, and a metabolic oncogene ( 19,20 ). Therefore, FAS has been considered as a potential target for the development of anti-obesity and anti-cancer drugs (21)(22)(23)(24)(25). Expression of FAS is transcriptionally regulated by the sterol regulatory element-binding protein-1c (SREBP-1c) and by upstream stimulatory factors 1 and 2 (USF1 and USF2) in response to feeding or to insulin ( 26,27 ). So far, however, nothing is known about the posttranslational modifi cation of FAS except that it is ubiquitinated ( 28,29 ).NO is a critical signaling molecule that is involved in a number of physiological and pathological processes. When overproduced, NO is known to have harmful effects on cell function and survival ( 30-32 ). In contrast, within the physiological concentration range, NO plays a critical role as a regulator of cellular signaling pathways ( 33-35 ). A major mechanism mediating the biological function of NO is protein S-nitrosylation, a posttranslational modifi cation of proteins involving the addition of an NO + to a cysteine thiol group of the proteins. Therefore, under physiological conditions, S-nitrosylation can affect a number of cellular signaling pathways by inducing conformational changes of the protein and affecting protein-protein interactions and protein functions (36)(37)(38)(39). NO is reported to improve the ␤ -oxidation of fatty acids through reversible protein S-nitrosylation ( 40 ). NO is also known to impair the antilipolytic action of insulin in obesity through S-nitrosylation ( 41 ) and to enhance adipogenesis in primary human preadipocytes ( 42 ). However, little is known about the target proteins of S-nitrosylation during adipogenesis.Abstract NO regulates a variety of physiological processes, including cell proliferation, differentiation, and infl ammation. S-nitrosylation, a NO-mediated reversible protein modifi cation, leads to changes in the activity and function of proteins. In particular, the role of S-nitrosylation during adipogenesis is largely unknown. We hypothesized that the normal physiological levels of NO, but not the excess levels generated under severe conditions, such as infl ammation, may be critically involved in the proper regulation of adipogenesis. We found that endogenous S-nitrosylation of proteins was required for adipocyte differentiation. By performing a biotin-switch assay, we identifi ed FAS, a key lipogenic enzyme in adipocytes, as a target of S-nitrosylation during adipogenesis. Interestingly, we also observed that the dimerization of FAS increased in parallel with the amount of S-nitrosylated FAS during adipogenesis. FAS, which is highly expressed in adipose tissue, liver, and lactating mammary glands, catalyzes the synthesis of palmitate from acetyl-CoA and malonyl-CoA in the presence of NADPH ( 1-3 ). FAS is active as a homodimer, and each monomer has seven separate functional domains, including malonyl/acetyltransferase, ␤ -ket...

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Nitric Oxide Regulates Mitochondrial Fatty Acid Metabolism Through Reversible Protein S -Nitrosylation

Cited by 230 publications

References 35 publications

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

The Expanding Landscape of the Thiol Redox Proteome

S-nitrosylation of fatty acid synthase regulates its activity through dimerization

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