Characterization of Nicotinamide Methyltransferase in Livers of Mice Bearing Ehrlich Ascites Tumors: Preferential Increase of Activity

Hanazawa, Yasuo; Sato, Kenichi; Kuroiwa, Namiko; Ogawa, Masako; Kuriyama, Atsuko; Asanagi, Mineko; Kato, Naoya; Moriyama, Yoichi; Horitsu, Keisuke; Fujimura, Shigefumi

doi:10.1159/000217868

Cited by 10 publications

(7 citation statements)

References 13 publications

(18 reference statements)

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“…23,[34][35][36] We have observed the enhancement of nucleic acid metabolism in the liver of tumor bearers. [37][38][39][40][41] Our previous study showed that hepatic NNMT activity continued to increase until death in mice bearing Ehrlich ascites tumor, 8) coupled with a decrease in hepatic catalase activity, a putative cachexia marker.…”

Section: Discussionmentioning

confidence: 99%

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Increased Hepatic Nicotinamide N‐Methyltransferase Activity as a Marker of Cancer Cachexia in Mice Bearing Colon 26 Adenocarcinoma

Okamura

Ohmura

Islam

et al. 1998

Japanese Journal of Cancer Research

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When a cachexigenic subclone (clone 20) of murine colon 26 adenocarcinoma was transplanted into female BALB/c mice, hepatic NNMT activity continued to increase until death in proportion to progressive carcass weight loss, a marker of cancer cachexia. On the other hand, noncachexigenic subclone (clone 5)-transplanted mice showed neither increase of NNMT activity nor carcass weight loss. Among cytostatic fluorinated pyrimidines, 5′ ′ ′ ′-dFUrd could inhibit the increase of NNMT activity and prevent weight loss in mice bearing clone 20. On the other hand, 2′ ′ ′ ′-dFUrd did not show these effects. 5-FUra and Tegafur inhibited the increase of NNMT activity at higher concentrations. These findings suggest that the levels of hepatic NNMT activity are closely associated with the degree of weight loss, and they appear to be a useful marker of cancer cachexia. Key words:Nicotinamide N-methyltransferase -Cancer cachexia -Liver -Colon 26 adenocarcinoma Ado-Met:NNMT (EC 2.1.1.1) catalyzes the N-methylation of nicotinamide and other pyridines.1) Ado-Met functions as a methyl donor for this reaction. NNMT is predominantly localized in the mammalian liver. 2-4)Recently, the NNMT gene was cloned and characterized. 5)Cancer cachexia is a complex syndrome characterized by body weight loss, anorexia, depletion of muscle and fat tissue, anemia and some altered blood metabolic parameters (e.g., hypoglycemia), etc. 6) Cancer cachexia is responsible for both decreased response to therapy and shortened survival. 7)Our previous study showed that hepatic NNMT activity increased after inoculation of various tumors into mice. 8)However, the mechanisms by which NNMT activity increases are not yet understood.Colon 26 adenocarcinoma is a chemically induced, murine colon-adenocarcinoma cell line.9) This tumor has been shown to induce marked cachexia (estimated in terms of carcass weight loss) in mice when the tumor mass is still relatively small, a situation similar to that found clinically. 10,11) There are two subclones of colon 26 adenocarcinoma; one is clone 20 with a remarkable cachexia-inducing potency, and the other is clone 5 without such potency. 12)In order to determine the relationship between the level of hepatic NNMT activity and the degree of cancer cachexia, we examined these parameters in a murine model using the aforementioned two clones. In the mice bearing the original colon 26 adenocarcinoma, cachexia was prevented by 5′-dFUrd in spite of the ineffectiveness of many other cytostatics.13) Thus, we examined whether levels of NNMT activity were correlated with the prevention of cachexia by 5′-dFUrd in this model. The present study showed that there was a direct correlation between levels of hepatic NNMT activity and the degree of cancer cachexia. MATERIALS AND METHODS Chemicals[ 3 H-methyl]Ado-Met (80 Ci/mmol) was purchased from Amersham International plc, Buckinghamshire, UK. Nicotinamide and 1-methylnicotinamide chloride were from Sigma, St. Louis, MO. 5′-dFUrd was donated by Nippon Roche K. K., Tokyo. 2′-dFUrd and 5-FUra we...

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Section: Discussionmentioning

confidence: 99%

“…7) Our previous study showed that hepatic NNMT activity increased after inoculation of various tumors into mice. 8) However, the mechanisms by which NNMT activity increases are not yet understood.…”

mentioning

confidence: 99%

Increased Hepatic Nicotinamide N‐Methyltransferase Activity as a Marker of Cancer Cachexia in Mice Bearing Colon 26 Adenocarcinoma

Okamura

Ohmura

Islam

et al. 1998

Japanese Journal of Cancer Research

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“…NNMT is a cytosolic enzyme with 29kDa molecular weight [3]. Although NNMT is mainly expressed in the liver in healthy tissues [17,18] low NNMT expression has been detected in the brain, lung, heart, kidney, skeletal muscle and placenta [7].…”

Section: Nnmt Expressionmentioning

confidence: 99%

“…Nicotinamide N-methyltransferase (NNMT) is a cytoplasmic enzyme in the N-methyltransferase family which catalyzes the N-methylation of pyridine, nicotinamide and structurally related compounds using S-adenosylmethionine (SAM) as the methyl donor [1][2][3][4][5]. NNMT is implicated in the regulation of multiple metabolic pathways in tissues, such as adipose and liver, through the consumption of methyl donors and the generation of active metabolites [6].…”

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Nicotinamide N-methyltransferase as a potential marker for cancer

Lu¹,

Long²

2018

neo

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Cancer is the main leading cause of death in the world, although it has been made noteworthy advances in cancer research in the past decades. Early detection of cancer is extremely important in improving the chances of successful therapy. Thus, it is urgently needed to make further efforts to explore novel tumor markers for treatment. Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme which catalyzes the N-methylation of nicotinamide to form 1-methylnicotinamide (1-MNA), and plays an important role in controlling the intracellular concentration of nicotinamide. Nicotinamide, the precursor to NAD+, is an important cofactor that associates cellular redox states with energy metabolism. Growing evidence shows that NNMT protein levels are elevated in a variety of human cancers, and increased NNMT expression has been linked to tumor aggressiveness. This paper presents a review for the role of NNMT expressed in a series of human cancers and the regulating mechanism involved, and offers its potential value of NNMT in cancer detection and treatment.

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“…Abnormal expression of NNMT was observed in many disease situations (7)(8)(9)(10)(11)(12)(13). For example, NNMT is overexpressed in the parkinsonian cerebellum.…”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase Inhibitor Depsipeptide Represses Nicotinamide N-Methyltransferase and Hepatocyte Nuclear Factor-1βGene Expression in Human Papillary Thyroid Cancer Cells

Hershman

2006

Thyroid

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Nicotinamide N-methyltransferase (NNMT) catalyzes N-methylation of nicotinamide and other structural analogues. NNMT gene expression is enhanced in many papillary thyroid cancer cells and activated by hepatocyte nuclear factor (HNF)-1beta. In this work, we studied the effects of depsipeptide, a histone deacetylase inhibitor, on NNMT gene expression in BHP 18-21 papillary thyroid cancer cells. Depsipeptide reduced NNMT mRNA level in a dose-dependent and time-dependent manner as determined by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). In contrast, expression of the sodium iodide symporter (NIS), a gene with differentiated function, waas enhanced in the treated cells. NNMT protein level determined by Western blot analysis and NNMT catalytic activity was also reduced significantly in the depsipeptide-treated cells. To study the mechanism of NNMT gene repression by depsipeptide, effects of depsipeptide on NNMT promoter activity were determined by luciferase reporter gene assay. NNMT promoter activity was significantly reduced in the HNF-1beta-positive BHP 18-21 cells but not in the HNF-1beta-negative BHP 14-9 papillary cancer cells. A mutant reporter construct with mutations in a HNF-1 site in the NNMT basal promoter region did not respond to depsipeptide in both HNF-1beta protein levels, and abolished activity of DNA binding to the HNF-1 site in the NNMT promoter region. Protein synthesis inhibitor cycloheximide and proteasome inhibitor MG-132 enhanced HNF-1beta stability in the depsipeptide-treated cells. In summary, depsipeptide represses NNMT and HNF-1beta gene expression in some papillary thyroid cancer cells. the repression of NNMT by depsipeptide is at the transcription level through downregulation of transcription activator HNF-1beta.

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Characterization of Nicotinamide Methyltransferase in Livers of Mice Bearing Ehrlich Ascites Tumors: Preferential Increase of Activity

Cited by 10 publications

References 13 publications

Increased Hepatic Nicotinamide N‐Methyltransferase Activity as a Marker of Cancer Cachexia in Mice Bearing Colon 26 Adenocarcinoma

Increased Hepatic Nicotinamide N‐Methyltransferase Activity as a Marker of Cancer Cachexia in Mice Bearing Colon 26 Adenocarcinoma

Nicotinamide N-methyltransferase as a potential marker for cancer

Histone Deacetylase Inhibitor Depsipeptide Represses Nicotinamide N-Methyltransferase and Hepatocyte Nuclear Factor-1βGene Expression in Human Papillary Thyroid Cancer Cells

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