NAD⁺ repletion with niacin counteracts cancer cachexia
|Author:||Beltrà, Marc1; Pöllänen, Noora2; Fornelli, Claudia1;|
1Experimental Medicine and Clinical Pathology Unit, Department of Clinical and Biological Sciences, University of Torino, Turin, Italy
2Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
3Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
4Faculty of Sport and Health Sciences, NeuroMuscular Research Center, University of Jyväskylä, Jyväskylä, Finland
5Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Turin, Italy
6Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
7Department of Biomedical Sciences, University of Padova, Padova, Italy
8CIR-MYO Myology Center, University of Padova, Padova, Italy
9Veneto Institute of Molecular Medicine, Padova, Italy
10Wihuri Research Institute, Helsinki, Finland
11Study Centre for Neurodegeneration, University of Padova (CESNE), Padova, Italy
12Research Unit of Biomedicine and Internal Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland
13Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
|Online Access:||PDF Full Text (PDF, 4.7 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe20230921134573
|Publish Date:|| 2023-09-21
Cachexia is a debilitating wasting syndrome and highly prevalent comorbidity in cancer patients. It manifests especially with energy and mitochondrial metabolism aberrations that promote tissue wasting. We recently identified nicotinamide adenine dinucleotide (NAD⁺) loss to associate with muscle mitochondrial dysfunction in cancer hosts. In this study we confirm that depletion of NAD⁺ and downregulation of Nrk2, an NAD⁺ biosynthetic enzyme, are common features of severe cachexia in different mouse models. Testing NAD⁺ repletion therapy in cachectic mice reveals that NAD⁺ precursor, vitamin B3 niacin, efficiently corrects tissue NAD⁺ levels, improves mitochondrial metabolism and ameliorates cancer- and chemotherapy-induced cachexia. In a clinical setting, we show that muscle NRK2 is downregulated in cancer patients. The low expression of NRK2 correlates with metabolic abnormalities underscoring the significance of NAD⁺ in the pathophysiology of human cancer cachexia. Overall, our results propose NAD⁺ metabolism as a therapy target for cachectic cancer patients.
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
This work was supported by Fondazione AIRC (IG 2018—ID. 21963 project, PI: F.P.), the Finnish Cancer Foundation, Finnish Cancer Center FICAN South (PIs: E.P. and Dr. Tommi Järvinen, respectively), the Academy of Finland (profi6 336449 to E.P.), The Finnish Medical Foundation (doctoral research grant to N.P.), and by two post-doctoral Fellowships from Fondazione Umberto Veronesi (ID2496 and ID3519 to R.S).
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