Nicotinamide N-Methyltransferase Remodeled Cell Metabolism and Aggravated Proinflammatory Responses by Activating STAT3/IL1β/PGE₂ Pathway

Abstract

Nicotinamide N-methyltransferase (NNMT) is a cytosolic methyltransferase, catalyzing N-methylation of nicotinamide (NAM) to form 1-methylnicotinamide (1-MNAM), in which S-adenosyl-l-methionine (SAM) is the methyl donor. It has been well documented that NNMT is elevated in multiple cancers and promotes tumor aggressiveness. In the present study, we investigated the effects of NNMT overexpression on cellular metabolism and proinflammatory responses. We found that NNMT overexpression reduced NAD+ and SAM levels, and activated the STAT3 signaling pathway. Consequently, STAT3 activation upregulated interleukin 1β (IL1β) and cyclooxygenase-2 (COX2), leading to prostaglandin E2 (PGE2) accumulation. On the other hand, NNMT downregulated 15-hydroxyprostaglandin dehydrogenase (15-PGDH) which catalyzes PGE2 into inactive molecules. Moreover, secretomic data indicated that NNMT promoted secretion of collagens, pro-inflammatory cytokines, and extracellular matrix proteins, confirming NNMT aggravated inflammatory responses to promote cell growth, migration, epithelial-mesenchymal transition (EMT), and chemoresistance. Taken together, we showed that NNMT played a pro-inflammatory role in cancer cells by activating the STAT3/IL1β/PGE2 axis and proposed that NNMT was a potential therapeutic target for cancer treatment.

Molecular Mechanisms of IL18 in Disease

“…Some reports have linked Nnmt and IL18 with cancer progression through the STAT3/IL1β pathway [42]. Our microarray analysis showed that the expression of Nnmt is significantly decreased in Il18 −/− mice.…”

Propionate reinforces epithelial identity and reduces aggressiveness of lung carcinoma

“…With regard to EMT transcription factors (EMT‐TFs), an overall and consistent reduction in the level of ZEB1, ZEB2, TWIST1 and (to a minimal extent) SLUG was observed with SP treatment in the 72 h time course, while SNAIL was found up‐regulated, indicating the potential supporting role of EMT‐TFs inhibition to EMT reversal (Appendix Fig S2D). The EMT inhibition by SP was further validated by additional EMT‐specific marker, NNMT (Shaul et al , 2014; Yang et al , 2022) (Appendix Fig S2E). Finally, mass spectrometry analysis of A549 cells treated with SP confirmed a significant increase in the intracellular propionate level (~27 folds) indicating the cellular uptake of exogenously supplemented propionate (Fig EV1H).…”

Metabolomics study of graphene nuangong acupoint plaster for primary dysmenorrhea

“…1-Methylnicotinamide is a direct metabolite of niacin and has various immune-regulatory properties, and it can inhibit the activation of the NLRP3 inflammasome by regulating reactive oxygen species levels [ 46 ]. Moreover, niacin is catalyzed by nicotinamide N-methyltransferase to generate 1-Methylnicotinamide, and overexpression of nicotinamide N-methyltransferase can activate the STAT3/IL1β/PGE2 pathway, leading to worsened inflammatory reactions [ 47 ]. Compared to the model group rats, there was a significant decrease in 1-Methylnicotinamide in the uteri of the graphene nuangong acupoint plaster group rats.…”