Nicotinamide N-Methyltransferase in Acquisition of Stem Cell Properties and Therapy Resistance in Cancer

Scientific paper - Review paper

• Author: Renata Novak Kujundžić
• Author: Marin Prpić
• Author: Nikola Đaković
• Author: Nina Dabelić
• Author: Marko Tomljanović
• Author: Anamarija Mojzeš
• Author: Ana Fröbe
• Author: Koraljka Gall Trošelj
• Author's institution: Ruđer Bošković Institute
• Author's institution: (Sestre milosrdnice University Hospital Center)
• Author's institution: University of Zagreb; School of Dental Medicine
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Dental Medicine

Abstract (english)

The activity of nicotinamide N-methyltransferase (NNMT) is tightly linked to the maintenance of the nicotinamide adenine dinucleotide (NAD+) level. This enzyme catalyzes methylation of nicotinamide (NAM) into methyl nicotinamide (MNAM), which is either excreted or further metabolized to N1-methyl-2-pyridone-5-carboxamide (2-PY) and H2O2. Enzymatic activity of NNMT is important for the prevention of NAM-mediated inhibition of NAD+-consuming enzymes poly–adenosine -diphosphate (ADP), ribose polymerases (PARPs), and sirtuins (SIRTs). Inappropriately high expression and activity of NNMT, commonly present in various types of cancer, has the potential to disrupt NAD+ homeostasis and cellular methylation potential. Largely overlooked, in the context of cancer, is the inhibitory effect of 2-PY on PARP-1 activity, which abrogates NNMT’s positive effect on cellular NAD+ flux by stalling liberation of NAM and reducing NAD+ synthesis in the salvage pathway. This review describes, and discusses, the mechanisms by which NNMT promotes NAD+ depletion and epigenetic reprogramming, leading to the development of metabolic plasticity, evasion of a major tumor suppressive process of cellular senescence, and acquisition of stem cell properties. All these phenomena are related to therapy resistance and worse clinical outcomes.

• Keywords (english): nicotinamide N-methyltransferase; nicotinamide adenine dinucleotide; aldehyde oxidase; cancer; epigenetic reprogramming; senescence; stem cell properties; therapy resistance
• Language: english
• Publication type: Scientific paper - Review paper
• Publication status: Published
• Peer review: Peer review - international
• Publication version: Published version
• Journal title: International Journal of Molecular Sciences
• Numbering: vol. 22, no. 11, 5681
• e-ISSN: 1422-0067
• DOI: https://doi.org/10.3390/ijms22115681
• URN:NBN: urn:nbn:hr:127:274723
• Publication: 2021-05-26
• Document URL: https://www.mdpi.com/1422-0067/22/11/5681
• Type of resource: Text
• Access conditions: Open access
• Created on: 2022-11-10 10:23:43