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 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.
Highlights
We introduce a new player in the evolution of the cancer phenotype—nicotinamide Nmethyltransferase (NNMT)—and discuss the evidence which places Nicotinamide N-methyltransferase (NNMT) in the centre of a web of pathways which promotes the metabolic and cellular changes observed in many cancer cells
No study has linked these effects to increased phosphorylation and activation of Akt. Pathways such as the ASK1-p38-MAPK pathway have been implicated in NNMT-mediated resistance of colorectal cancer cells to 5-FU [125], given the strong cytoprotective effects of Akt signalling, along with the well-documented regulation of Akt phosphorylation demonstrated by us and others in a wide variety of cancers, it is likely that the NNMT–Akt axis is heavily involved in acquired drug resistance
Its link to SAM usage [234], it was long thought that the role of NNMT was merely as a component of Phase II metabolism, N-methylating pyridine-containing compounds and regulating cellular nicotinamide levels [209]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. In neoplastic cells, energy metabolism undergoes a metabolic shift, called the Warburg effect, whereby cells rely predominantly upon glycolysis for their energy needs (for a full in-depth review of the Warburg effect in cancer, see [1]) This change in ATP supply source reduces the number of ATP molecules produced per glucose molecule from a (theoretical) maximum of 38 to 2 [2]; such a marked decrease seems counterproductive to cell survival at first glance. Mitochondrial oxidation of pyruvate via the Krebs cycle and the mitochondrial respiratory chain is reduced, mediated by increased expression of lactate dehydrogenase A and pyruvate kinase M2 which shuttles pyruvate into lactate production. We will discuss the challenges faced in designing cancer therapeutics based upon NNMT and show that NNMT-based therapies are potentially a macrorevolution in cancer treatment
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