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Biomolecules
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Functions of Nicotinamide N-Methyltransferase in Cancer
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Functions of Nicotinamide N-Methyltransferase in Cancer

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Enzymology".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 23506

Special Issue Editor

Dr. Davide Sartini

E-Mail Website
Guest Editor
Department of Clinical Sciences, Polytechnic University of Marche, via Tronto 10/a, 60126 Ancona, Italy
Interests: biochemistry; molecular biology; medicinal chemistry; cell biology; molecular oncology; tumor biomarker discovery

Special Issue Information

Dear Colleagues,

A Special Issue on the “Functions of Nicotinamide N-Methyltransferase in Cancer” is being prepared for the journal Biomolecules.

Human nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the N-methylation of nicotinamide, pyridines, and other structural analogues, using S-adenosyl-L-methionine as the methyl donor. NNMT plays a fundamental role in nicotinamide catabolism, as well as in the biotransformation and detoxification of many xenobiotics, as it belongs to the group of phase II metabolizing enzymes. NNMT is mainly expressed in the liver, and its upregulation has been found in a wide variety of solid cancers, including papillary thyroid carcinoma, colorectal cancer, gastric cancer, lung cancer, renal cell carcinoma, bladder cancer, oral carcinoma, and melanoma. However, the significance of NNMT overexpression in cancer cells, as well as the cellular effects exerted by this dysregulation, have not been totally elucidated. Collectively, the data reported to date seem to demonstrate that NNMT could be involved in cell proliferation, viability, and migration; metastatic potential; as well as tumor cell sensitivity to chemotherapeutic treatment. Moreover, these results suggest an interesting role played by NNMT as a potential diagnostic and/or prognostic biomarker, supporting the hypothesis that it could represent a promising molecular target for effective anticancer therapy.

Dr. Davide Sartini
Guest Editor

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Keywords

  • nicotinamide N-methyltransferase
  • S-adenosyl-L-methionine
  • nicotinamide
  • diagnostic and prognostic marker
  • molecular target
  • targeted therapy
  • cancer cell phenotype

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Published Papers (5 papers)

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Research

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20 pages, 2050 KiB  
Article
Esterase-Sensitive Prodrugs of a Potent Bisubstrate Inhibitor of Nicotinamide N-Methyltransferase (NNMT) Display Cellular Activity
by Matthijs J. van Haren, Yongzhi Gao, Ned Buijs, Roberto Campagna, Davide Sartini, Monica Emanuelli, Lukasz Mateuszuk, Agnieszka Kij, Stefan Chlopicki, Pol Escudé Martinez de Castilla, Raymond Schiffelers and Nathaniel I. Martin
Biomolecules 2021, 11(9), 1357; https://doi.org/10.3390/biom11091357 - 14 Sep 2021
Cited by 27 | Viewed by 4374
Abstract
A recently discovered bisubstrate inhibitor of Nicotinamide N-methyltransferase (NNMT) was found to be highly potent in biochemical assays with a single digit nanomolar IC50 value but lacking in cellular activity. We, here, report a prodrug strategy designed to translate the observed [...] Read more.
A recently discovered bisubstrate inhibitor of Nicotinamide N-methyltransferase (NNMT) was found to be highly potent in biochemical assays with a single digit nanomolar IC50 value but lacking in cellular activity. We, here, report a prodrug strategy designed to translate the observed potent biochemical inhibitory activity of this inhibitor into strong cellular activity. This prodrug strategy relies on the temporary protection of the amine and carboxylic acid moieties of the highly polar amino acid side chain present in the bisubstrate inhibitor. The modification of the carboxylic acid into a range of esters in the absence or presence of a trimethyl-lock (TML) amine protecting group yielded a range of candidate prodrugs. Based on the stability in an aqueous buffer, and the confirmed esterase-dependent conversion to the parent compound, the isopropyl ester was selected as the preferred acid prodrug. The isopropyl ester and isopropyl ester-TML prodrugs exhibit improved cell permeability, which also translates to significantly enhanced cellular activity as established using assays designed to measure the enzymatic activity of NNMT in live cells. Full article
(This article belongs to the Special Issue Functions of Nicotinamide N-Methyltransferase in Cancer)
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19 pages, 5556 KiB  
Article
Curcumin Reverses NNMT-Induced 5-Fluorouracil Resistance via Increasing ROS and Cell Cycle Arrest in Colorectal Cancer Cells
by Guoli Li, Sining Fang, Xiao Shao, Yejia Li, Qingchao Tong, Beibei Kong, Lifen Chen, Yanzhong Wang, Jun Yang, Haitao Yu, Xinyou Xie and Jun Zhang
Biomolecules 2021, 11(9), 1295; https://doi.org/10.3390/biom11091295 - 31 Aug 2021
Cited by 46 | Viewed by 3564
Abstract
Nicotinamide N-methyltransferase (NNMT) plays multiple roles in improving the aggressiveness of colorectal cancer (CRC) and enhancing resistance to 5-Fluorouracil (5-FU), making it an attractive therapeutic target. Curcumin (Cur) is a promising natural compound, exhibiting multiple antitumor effects and potentiating the effect of [...] Read more.
Nicotinamide N-methyltransferase (NNMT) plays multiple roles in improving the aggressiveness of colorectal cancer (CRC) and enhancing resistance to 5-Fluorouracil (5-FU), making it an attractive therapeutic target. Curcumin (Cur) is a promising natural compound, exhibiting multiple antitumor effects and potentiating the effect of 5-FU. The aim of the present study is to explore the effect of Cur on attenuating NNMT-induced resistance to 5-FU in CRC. A panel of CRC cell lines with different NNMT expressions are used to characterize the effect of Cur. Herein, it is observed that Cur can depress the expression of NNMT and p-STAT3 in CRC cells. Furthermore, Cur can induce inhibition of cell proliferation, G2/M phase cell cycle arrest, and reactive oxygen species (ROS) generation, especially in high-NNMT-expression CRC cell lines. Cur can also re-sensitize high-NNMT-expression CRC cells to 5-FU both in vitro and in vivo. In summary, it is proposed that Cur can reverse NNMT-induced cell proliferation and 5-FU resistance through ROS generation and cell cycle arrest. Given that Cur has long been used, we suppose that Cur is a promising anticancer drug candidate with minimal side effects for human CRC therapy and can attenuate NNMT-induced resistance to 5-FU. Full article
(This article belongs to the Special Issue Functions of Nicotinamide N-Methyltransferase in Cancer)
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Review

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15 pages, 1138 KiB  
Review
Nicotinamide N-Methyltransferase in Head and Neck Tumors: A Comprehensive Review
by Lucrezia Togni, Marco Mascitti, Davide Sartini, Roberto Campagna, Valentina Pozzi, Eleonora Salvolini, Annamaria Offidani, Andrea Santarelli and Monica Emanuelli
Biomolecules 2021, 11(11), 1594; https://doi.org/10.3390/biom11111594 - 28 Oct 2021
Cited by 25 | Viewed by 2700
Abstract
The head and neck tumors (HNT) are a heterogeneous group of diseases ranging from benign to malignant lesions, with distinctive molecular and clinical behaviors. Several studies have highlighted the presence of an altered metabolic phenotype in HNT, such as the upregulation of nicotinamide [...] Read more.
The head and neck tumors (HNT) are a heterogeneous group of diseases ranging from benign to malignant lesions, with distinctive molecular and clinical behaviors. Several studies have highlighted the presence of an altered metabolic phenotype in HNT, such as the upregulation of nicotinamide N-methyltransferase (NNMT). However, its biological effects have not been completely disclosed and the role of NNMT in cancer cell metabolism remains unclear. Therefore, this comprehensive review aims to evaluate the available literature regarding the biological, diagnostic, and prognostic role of NNMT in HNT. NNMT was shown to be significantly overexpressed in all of the evaluated HNT types. Moreover, its upregulation has been correlated with cancer cell migration and adverse clinical outcomes, such as high-pathological stage, lymph node metastasis, and locoregional recurrences. However, in oral squamous cell carcinoma (OSCC) these associations are still debated, and several studies have failed to demonstrate the prognostic significance of NNMT. The shRNA-mediated gene silencing efficiently suppressed the NNMT gene expression and exhibited a clear inhibitory effect on cell proliferation, promoting the expression of apoptosis-related proteins and modulating the cell cycle. NNMT could represent a new molecular biomarker and a new target of molecular-based therapy, although further studies on larger patient cohorts are needed to explore its biological role in HNT. Full article
(This article belongs to the Special Issue Functions of Nicotinamide N-Methyltransferase in Cancer)
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29 pages, 2598 KiB  
Review
Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution
by Richard B. Parsons and Paul D. Facey
Biomolecules 2021, 11(10), 1418; https://doi.org/10.3390/biom11101418 - 28 Sep 2021
Cited by 15 | Viewed by 8831
Abstract
Nicotinamide N-methyltransferase (NNMT) has progressed from being considered merely a Phase II metabolic enzyme to one with a central role in cell function and energy metabolism. Over the last three decades, a significant body of evidence has accumulated which clearly demonstrates a [...] Read more.
Nicotinamide N-methyltransferase (NNMT) has progressed from being considered merely a Phase II metabolic enzyme to one with a central role in cell function and energy metabolism. Over the last three decades, a significant body of evidence has accumulated which clearly demonstrates a central role for NNMT in cancer survival, metastasis, and drug resistance. In this review, we discuss the evidence supporting a role for NNMT in the progression of the cancer phenotype and how it achieves this by driving the activity of pro-oncogenic NAD+-consuming enzymes. We also describe how increased NNMT activity supports the Warburg effect and how it promotes oncogenic changes in gene expression. We discuss the regulation of NNMT activity in cancer cells by both post-translational modification of the enzyme and transcription factor binding to the NNMT gene, and describe for the first time three long non-coding RNAs which may play a role in the regulation of NNMT transcription. We complete the review by discussing the development of novel anti-cancer therapeutics which target NNMT and provide insight into how NNMT-based therapies may be best employed clinically. Full article
(This article belongs to the Special Issue Functions of Nicotinamide N-Methyltransferase in Cancer)
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13 pages, 614 KiB  
Review
The Utility of Nicotinamide N-Methyltransferase as a Potential Biomarker to Predict the Oncological Outcomes for Urological Cancers: An Update
by Roberto Campagna, Valentina Pozzi, Graziana Spinelli, Davide Sartini, Giulio Milanese, Andrea Benedetto Galosi and Monica Emanuelli
Biomolecules 2021, 11(8), 1214; https://doi.org/10.3390/biom11081214 - 16 Aug 2021
Cited by 25 | Viewed by 2886
Abstract
Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation reaction of nicotinamide, using S-adenosyl-L-methionine as the methyl donor. Enzyme overexpression has been described in many non-neoplastic diseases, as well as in a wide range of solid malignancies. This review aims to report and discuss evidence available [...] Read more.
Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation reaction of nicotinamide, using S-adenosyl-L-methionine as the methyl donor. Enzyme overexpression has been described in many non-neoplastic diseases, as well as in a wide range of solid malignancies. This review aims to report and discuss evidence available in scientific literature, dealing with NNMT expression and the potential involvement in main urologic neoplasms, namely, renal, bladder and prostate cancers. Data illustrated in the cited studies clearly demonstrated NNMT upregulation (pathological vs. normal tissue) in association with these aforementioned tumors. In addition to this, enzyme levels were also found to correlate with key prognostic parameters and patient survival. Interestingly, NNMT overexpression also emerged in peripheral body fluids, such as blood and urine, thus leading to candidate the enzyme as promising biomarker for the early and non-invasive detection of these cancers. Examined results undoubtedly showed NNMT as having the capacity to promote cell proliferation, migration and invasiveness, as well as its potential participation in fundamental events highlighting cancer progression, metastasis and resistance to chemo- and radiotherapy. In the light of this evidence, it is reasonable to attribute to NNMT a promising role as a potential biomarker for the diagnosis and prognosis of urologic neoplasms, as well as a molecular target for effective anti-cancer treatment. Full article
(This article belongs to the Special Issue Functions of Nicotinamide N-Methyltransferase in Cancer)
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