Leucine-rich diet induces a shift in tumour metabolism from glycolytic towards oxidative phosphorylation, reducing glucose consumption and metastasis in Walker-256 tumour-bearing rats

Leucine can stimulate protein synthesis in skeletal muscle, and recent studies have shown an increase in leucine-related mitochondrial biogenesis and oxidative phosphorylation capacity in muscle cells. However, leucine-related effects in tumour tissues are still poorly understood. Thus, we described...

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Published in:Scientific reports 2019-10, Vol.9 (1), p.15529-11, Article 15529
Main Authors: Viana, Laís Rosa, Tobar, Natália, Busanello, Estela Natacha Brandt, Marques, Ana Carolina, de Oliveira, Andre Gustavo, Lima, Tanes I, Machado, Gabrielly, Castelucci, Bianca Gazieri, Ramos, Celso Dario, Brunetto, Sérgio Q, Silveira, Leonardo Reis, Vercesi, Anibal Eugenio, Consonni, Sílvio Roberto, Gomes-Marcondes, Maria Cristina Cintra
Format: Article
Language:English
Subjects:
Amino acids
Animals
Apoptosis
Biopsy
Carcinoma 256, Walker - diet therapy
Carcinoma 256, Walker - metabolism
Carcinoma 256, Walker - pathology
Computed tomography
Diet
Electron microscopy
Female
Food, Formulated
Gene expression
Glucose - metabolism
Glycolysis
Glycolysis - drug effects
Leucine
Leucine - pharmacology
Metabolism
Metastases
Metastasis
Mitochondria
mRNA
Neoplasm Metastasis
Oxidative metabolism
Oxidative phosphorylation
Oxidative Phosphorylation - drug effects
Oxidative stress
Oxygen consumption
Phenotypes
Phosphorylation
Positron emission tomography
Protein biosynthesis
Proteins
Rats
Rats, Wistar
Skeletal muscle
Tumors
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Summary:Leucine can stimulate protein synthesis in skeletal muscle, and recent studies have shown an increase in leucine-related mitochondrial biogenesis and oxidative phosphorylation capacity in muscle cells. However, leucine-related effects in tumour tissues are still poorly understood. Thus, we described the effects of leucine in both in vivo and in vitro models of a Walker-256 tumour. Tumour-bearing Wistar rats were randomly distributed into a control group (W; normoprotein diet) and leucine group (LW; leucine-rich diet [normoprotein + 3% leucine]). After 20 days of tumour evolution, the animals underwent -fludeoxyglucose positron emission computed tomography ( F-FDG PET-CT) imaging, and after euthanasia, fresh tumour biopsy samples were taken for oxygen consumption rate measurements (Oroboros Oxygraph), electron microscopy analysis and RNA and protein extraction. Our main results from the LW group showed no tumour size change, lower tumour glucose ( F-FDG) uptake, and reduced metastatic sites. Furthermore, leucine stimulated a shift in tumour metabolism from glycolytic towards oxidative phosphorylation, higher mRNA and protein expression of oxidative phosphorylation components, and enhanced mitochondrial density/area even though the leucine-treated tumour had a higher number of apoptotic nuclei with increased oxidative stress. In summary, a leucine-rich diet directed Walker-256 tumour metabolism to a less glycolytic phenotype profile in which these metabolic alterations were associated with a decrease in tumour aggressiveness and reduction in the number of metastatic sites in rats fed a diet supplemented with this branched-chain amino acid.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-52112-w