Identification of Nicotinamide<i>N</i>-Methyltransferase as a Novel Serum Tumor Marker for Colorectal Cancer

Roeßler, Markus; Rollinger, Wolfgang; Palme, Stefan; Hagmann, Marie-Luise; Berndt, Peter; Engel, Alfred M.; Schneidinger, Bernd; Pfeffer, Michael; Andres, Herbert; Karl, J. Philip; Bodenmüller, Heinz; Rüschoff, Josef; Henkel, Thomas; Rohr, Gerhard; Rossol, S.; Rösch, Wolfgang; Langen, Hanno; Zolg, Werner; Tacke, Michael

doi:10.1158/1078-0432.ccr-05-0983

Cited by 171 publications

(181 citation statements)

References 41 publications

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“…Several diseases are associated with abnormal nicotinamide metabolism resulting in the production of elevated levels of N-methylnicotinamide; these include Parkinson's disease and hepatic cirrhosis (Cuomo et al, 1994;Parsons et al, 2002). Recently, NNMT was reported as novel serum markers of human colorectal cancer as potential candidates for noninvasive detection of early colorectal neoplasm (Roessler et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of nicotinamide N-methyltransferase in gastric cancer tissues and its potential post-translational modification

Lim

Cho²,

Kim³

et al. 2006

Exp Mol Med

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Gastric cancer is one of the most common cancers worldwide. The purpose of this study was to find out potential markers for gastric cancer. Tumor and normal tissues from 152 gastric cancer cases were analyzed by two-dimensional gel electrophoresis (2-DE). The images of silver stained gels were analyzed and statistical analysis of spot intensities revealed that spot 4262 showed higher expression (5.7-fold increase) in cancer tissues than in normal tissues (P ＜0.001). It was identified by peptide mass fingerprinting as nicotinamide N-methyltransferase (NNMT). A monoclonal antibody with a detection limit down to 10 ng was produced against NNMT in mouse. Using the prepared monoclonal antibody, western blot analysis of NNMT was performed for gastric tissues from 15 gastric cancer patients and two gastric ulcer patients. The results corroborated those of 2-DE experiments. A single spot was detected in gastric ulcer tissues while four to five spots were detected in gastric cancer tissues. In cancer tissues, two additional spots of acidic and basic form were mainly detected on 2-DE gels. This suggests that NNMT receives a post-translational modification in cancer-specific manner.

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Section: Discussionmentioning

confidence: 99%

Overexpression of nicotinamide N-methyltransferase in gastric cancer tissues and its potential post-translational modification

Lim

Cho²,

Kim³

et al. 2006

Exp Mol Med

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“…Interestingly, many cancers have been reported to have an enhanced expression of NNMT. [22][23][24][25] As NNMT activity is positively related to nicotinamide levels, as demonstrated by Riederer et al, 20 it is likely that elevated NNMT expression in cancers may therefore be related to excessive niacin intake.…”

Section: Discussionmentioning

confidence: 92%

“…NNMT, which is a key enzyme in the degradation of nicotinamide, is not only highly expressed in the liver, but also widely expressed in extrahepatic tissues, including adipose tissue, 20 skeletal muscle, 21 stomach, 22 colon, 23 kidney, 24 thyroid 25 and brain. 26 It is obvious that nicotinamide methylation may occur not only in the liver, but also in those extrahepatic tissues.…”

Section: Discussionmentioning

confidence: 99%

Excess nicotinamide inhibits methylation-mediated degradation of catecholamines in normotensives and hypertensives

Sun

Lun

et al. 2011

Hypertens Res

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Nicotinamide and catecholamines are both degraded by S-adenosylmethionine-dependent methylation. Whether excess nicotinamide affects the degradation of catecholamines is unknown. The aim of this study was to investigate the effect of nicotinamide on the methylation status of the body and methylation-mediated catecholamine degradation in both normotensives and hypertensives. The study was conducted in 19 normotensives and 27 hypertensives, using a nicotinamide-loading test (100 mg orally). Plasma nicotinamide, N 1 -methylnicotinamide, homocysteine (Hcy), betaine, norepinephrine, epinephrine, normetanephrine and metanephrine levels before and 5 h after nicotinamide loading were measured. Compared with normotensives, hypertensives had higher baseline (fasting) levels of plasma nicotinamide, Hcy and norepinephrine, but lower levels of plasma normetanephrine, a methylated norepinephrine derivative. Nicotinamide loading induced a significant increase in the levels of plasma N 1 -methylnicotinamide and norepinephrine, and a significant decrease in the levels of O-methylated epinephrine (metanephrine) and betaine, a major methyl donor, in both hypertensives and normotensives. Moreover, nicotinamide-loading significantly increased plasma Hcy levels, but decreased plasma normetanephrine levels in normotensives. The baseline levels of plasma epinephrine in hypertensives were similar to those of normotensives, but the post-nicotinamideloading levels of plasma epinephrine in hypertensives were higher than those of normotensives. This study demonstrated that excess nicotinamide might deplete the labile methyl pool, increase Hcy generation and inhibit catecholamine degradation. It also revealed that hypertensives had an abnormal methylation pattern, characterized by elevated fasting plasma levels of unmethylated substrates, nicotinamide, Hcy and norepinephrine. Therefore, it seems likely that high nicotinamide intake may be involved in the pathogenesis of Hcy-related cardiovascular disease.

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“…Moreover, heightened NNMT activity was reported in many types of cancer cells, including papillary thyroid cancer cells [47], renal carcinoma cells [49], human stomach adenocarcinoma cells [23], oral squamous carcinoma cells [38], colorectal cancer cells [35], and radio-resistant bladder cancer cells [24]. The upregulation of NMMT in cancer cells suggests a possible role for NMMT in tumor growth, migration, and metastasis [38,46].…”

Section: Introductionmentioning

confidence: 99%

“…The upregulation of NMMT in cancer cells suggests a possible role for NMMT in tumor growth, migration, and metastasis [38,46]. Indeed, it was hypothesized that NNMT activity in cancer cells or NNMT concentrations in serum may provide a useful biomarker in patients with cancer [35,37].…”

Section: Introductionmentioning

confidence: 99%

Activation of nicotinamide N-methyltrasferase and increased formation of 1-methylnicotinamide (MNA) in atherosclerosis

Mateuszuk

Хомич²,

Słomińska

et al. 2009

Pharmacological Reports

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Abstract:Nicotinamide N-methyltrasferase (NMMT) catalyzes the conversion of nicotinamide (NA) to 1-methylnicotinamide (MNA). Recent studies have reported that exogenous MNA exerts anti-thrombotic and anti-inflammatory activity, suggesting that endogenous NMMT-derived MNA may play a biological role in the cardiovascular system. In the present study, we assayed changes in hepatic NNMT activity and MNA plasma levels along the progression of atherosclerosis in apoE/LDLR -/-mice, as compared to age-matched wild-type mice. Atherosclerosis progression in apoE/LDLR -/-mice was quantified in aortic root, while hepatic NNMT activity and MNA plasma concentrations were concomitantly measured in 2-, 3-, 4-, and 6-month-old mice. In apoE/LDLR -/-mice, atherosclerotic plaques developed in the aortic roots beginning at the age of 3 months and gradually increased in size, macrophage content, and inflammation intensity over time, as detected by Oil-Red O staining, CD68 immunostaining, and in situ zymography (MMP2/MMP9 activity). Hepatic NNMT activity was upregulated approximately two-fold in apoE/LDLR -/-mice by the age of 2 months, as compared to wild-type mice (1.03 ± 0.14 vs. 0.64 ± 0.23 pmol/min/mg, respectively). MNA plasma concentrations were also elevated approximately two-fold (0.30 ± 0.13 vs. 0.17 ± 0.04 mmol/l, respectively). As atherosclerosis progressed, hepatic NMMT activity and MNA plasma concentrations increased five-fold in 6-month-old apoE/LDLR -/-mice at the stage of advanced atherosclerotic plaques (NMMT activity: 2.29 ± 0.34 pmol/min/mg, MNA concentration: 1.083 ± 0.33 mmol/l). In summary, the present study demonstrated that the progression of vascular inflammation and atherosclerosis was associated with the upregulation of hepatic NNMT activity and subsequent increase in endogenous MNA plasma levels. Given the anti-thrombotic and anti-inflammatory properties of exogenous MNA, robust activation of an endogenous NA-MNA pathway in atherosclerosis may play an important compensatory role.

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Identification of NicotinamideN-Methyltransferase as a Novel Serum Tumor Marker for Colorectal Cancer

Abstract: It is proposed that NNMT serum levels may have significance in the early detection and in the management of patients with colorectal cancer.

Cited by 171 publications

References 41 publications

Overexpression of nicotinamide N-methyltransferase in gastric cancer tissues and its potential post-translational modification

Overexpression of nicotinamide N-methyltransferase in gastric cancer tissues and its potential post-translational modification

Excess nicotinamide inhibits methylation-mediated degradation of catecholamines in normotensives and hypertensives

Activation of nicotinamide N-methyltrasferase and increased formation of 1-methylnicotinamide (MNA) in atherosclerosis

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