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Background: The metabolic enzyme nicotinamide‐N‐methyltransferase (NNMT) is highly expressed in various cancer entities, suggesting tumour‐promoting functions. We systematically investigated NNMT expression and its metabolic interactions in clear cell renal cell carcinoma (ccRCC), a prominent RCC subtype with metabolic alterations, to elucidate its role as a drug target. Methods: NNMT expression was assessed in primary ccRCC (n = 134), non‐tumour tissue and ccRCC‐derived metastases (n = 145) by microarray analysis and/or immunohistochemistry. Findings were validated in The Cancer Genome Atlas (kidney renal clear cell carcinoma [KIRC], n = 452) and by single‐cell analysis. Expression was correlated with clinicopathological data and survival. Metabolic alterations in NNMT‐depleted cells were assessed by nontargeted/targeted metabolomics and extracellular flux analysis. The NNMT inhibitor (NNMTi) alone and in combination with the inhibitor 2‐deoxy‐D‐glucose for glycolysis and BPTES (bis‐2‐(5‐phenylacetamido‐1,3,4‐thiadiazol‐2‐yl)ethyl‐sulfide) for glutamine metabolism was investigated in RCC cell lines (786‐O, A498) and in two 2D ccRCC‐derived primary cultures and three 3D ccRCC air–liquid interface models. Results: NNMT protein was overexpressed in primary ccRCC (p = 1.32 × 10–16) and ccRCC‐derived metastases (p = 3.92 × 10–20), irrespective of metastatic location, versus non‐tumour tissue. Single‐cell data showed predominant NNMT expression in ccRCC and not in the tumour microenvironment. High NNMT expression in primary ccRCC correlated with worse survival in independent cohorts (primary RCC—hazard ratio [HR] = 4.3, 95% confidence interval [CI]: 1.5–12.4; KIRC—HR = 3.3, 95% CI: 2.0–5.4). NNMT depletion leads to intracellular glutamine accumulation, with negative effects on mitochondrial function and cell survival, while not affecting glycolysis or glutathione metabolism. At the gene level, NNMT‐depleted cells upregulate glycolysis, oxidative phosphorylation and apoptosis pathways. NNMTi alone or in combination with 2‐deoxy‐D‐glucose and BPTES resulted in inhibition of cell viability in ccRCC cell lines and primary tumour and metastasis‐derived models. In two out of three patient‐derived ccRCC air–liquid interface models, NNMTi treatment induced cytotoxicity. Conclusions: Since efficient glutamine utilisation, which is essential for ccRCC tumours, depends on NNMT, small‐molecule NNMT inhibitors provide a novel therapeutic strategy for ccRCC and act as sensitizers for combination therapies. [ABSTRACT FROM AUTHOR]

Chronic Helicobacter pylori infection is characterized by dense infiltration of the mucosa with neutrophilic granulocytes, lymphocytes, and monocytes/macrophages. Among these different cell types, T-lymphocytes are the most intriguing and crucial cells for the elimination of the bacteria. Previous studies have elucidated possible mechanisms on how bacteria could interfere with the human immune response and claimed that especially the secreted vacuolating toxin VacA may be responsible for the chronic persistence of the bacteria. Some of these results have to be interpreted with caution and may just describe in vitro phenomena; others may reveal promising facts. [ABSTRACT FROM AUTHOR]