Academic Journal
Nicotinamide‐N‐methyltransferase is a promising metabolic drug target for primary and metastatic clear cell renal cell carcinoma
| العنوان: | Nicotinamide‐N‐methyltransferase is a promising metabolic drug target for primary and metastatic clear cell renal cell carcinoma |
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| المؤلفون: | Reustle, Anna, Menig, Lena‐Sophie, Leuthold, Patrick, Hofmann, Ute, Stühler, Viktoria, Schmees, Christian, Becker, Michael, Haag, Mathias, Klumpp, Verena, Winter, Stefan, Büttner, Florian A., Rausch, Steffen, Hennenlotter, Jörg, Fend, Falko, Scharpf, Marcus, Stenzl, Arnulf, Bedke, Jens, Schwab, Matthias, Schaeffeler, Elke |
| المصدر: | Clinical and Translational Medicine ; volume 12, issue 6 ; ISSN 2001-1326 2001-1326 |
| بيانات النشر: | Wiley |
| سنة النشر: | 2022 |
| المجموعة: | Wiley Online Library (Open Access Articles via Crossref) |
| الوصف: | 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 ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1002/ctm2.883 |
| الاتاحة: | http://dx.doi.org/10.1002/ctm2.883 https://onlinelibrary.wiley.com/doi/pdf/10.1002/ctm2.883 https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ctm2.883 |
| Rights: | http://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: | edsbas.A5B939F1 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1002/ctm2.883 |
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