Leucine modulates the effect of Walker factor, a proteolysis-inducing factor-like protein from Walker tumours, on gene expression and cellular activity in C2C12 myotubes

Gonçalves, Estela Maria; Salomão, Emilianne Miguel; Marcondes, Maria Cristina Cintra Gomes

doi:10.1016/j.cyto.2013.05.018

Cited by 15 publications

(15 citation statements)

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“…Previous reports have provided evidence for the presence of these factors in the ascitic fluid and for their effective actions on protein degradation [18,34,[46][47][48]. We isolated proteolysis-induced factor (PIF) from the MAC16 ascitic fluid, as previous reported by Todorov and colleagues [49], and confirmed its strong effects on muscle protein synthesis and degradation [34,[49][50][51]. Similar results were found here where the A group exhibited impaired fetal weight and reduced placental weight as well as downregulation of pERK/MAPK, pIRS-1, and pmTOR protein expression.…”

Section: Discussionsupporting

confidence: 84%

“…Likewise, in response to tumor growth, the placental tissues had a higher protein expression of the 20S and 19S subunits, in line with an increase of protein catabolism. Moreover, PC2 and PC5 genes are related to the 20S proteasome subunit [40,41,48], and their increased genetic expression is commonly found during skeletal muscle wasting [40,41,51]. In addition to this fact, we observed enhanced PC5 gene expression in the placenta tissues of the MAC16 tumor-bearing group.…”

Section: Discussionmentioning

confidence: 48%

“…Several lines of evidence, including our previous reports, have demonstrated that leucine is the most effective amino acid for stimulating protein synthesis and decreasing catabolism in both in vivo and in vitro assays [23,24,27,51,[58][59][60].…”

Section: Discussionmentioning

confidence: 97%

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A Leucine-Rich Diet Modulates the Tumor-Induced Down-Regulation of the MAPK/ERK and PI3K/Akt/mTOR Signaling Pathways and Maintains the Expression of the Ubiquitin-Proteasome Pathway in the Placental Tissue of NMRI Mice1

Viana

Marcondes

2015

Biology of Reproduction

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Placental tissue injury is concomitant with tumor development. We investigated tumor-driven placental damage by tracing certain steps of the protein synthesis and degradation pathways under leucine-rich diet supplementation in MAC16 tumor-bearing mice. Cell signaling and ubiquitin-proteasome pathways were assessed in the placental tissues of pregnant mice, which were distributed into three groups on a control diet (pregnant control, tumor-bearing pregnant, and pregnant injected with MAC-ascitic fluid) and three other groups on a leucine-rich diet (pregnant, tumor-bearing pregnant, and pregnant injected with MAC-ascitic fluid). MAC tumor growth down-regulated the cell-signaling pathways of the placental tissue and decreased the levels of IRS-1, Akt/PKB, Erk/MAPK, mTOR, p70S6K, STAT3, and STAT6 phosphorylated proteins, as assessed by the multiplex Millipore Luminex assay. Leucine supplementation maintained the levels of these proteins within the established cell-signaling pathways. In the tumor-bearing group (MAC) only, the placental tissue showed increased PC5 mRNA expression, as assessed by quantitative RT-PCR, decreased 19S and 20S protein expression, as assessed by Western blot analysis, and decreased placental tyrosine levels, likely reflecting up-regulation of the ubiquitin-proteasome pathway. Similar effects were found in the pregnant injected with MAC-ascitic fluid group, confirming that the effects of the tumor were mimicked by MAC-ascitic fluid injection. Although tumor progression occurred, the degradation pathway-related protein levels were modulated under leucine-supplementation conditions. In conclusion, tumor evolution reduced the protein expression of the cell-signaling pathway associated with elevated protein degradation, thereby jeopardizing placental activity. Under the leucine-rich diet, the impact of cancer on placental function could be minimized by improving the cell-signaling activity and reducing the proteolytic process.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 48%

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A Leucine-Rich Diet Modulates the Tumor-Induced Down-Regulation of the MAPK/ERK and PI3K/Akt/mTOR Signaling Pathways and Maintains the Expression of the Ubiquitin-Proteasome Pathway in the Placental Tissue of NMRI Mice1

Viana

Marcondes

2015

Biology of Reproduction

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“…However, two KEGG modules were enriched in CRC microbiomes: leucine degradation (q=0.0148) and guanine nucleotide biosynthesis (q=0.0241; see online supplementary table S6). Leucine stimulates both protein synthesis and degradation,33 34 suggesting possible links between leucine metabolism and cancer. At the gene level, several KEGG orthologous groups showed significant associations with disease status (Wilcoxon rank-sum test, q<0.05; see online supplementary table S7).…”

Section: Resultsmentioning

confidence: 99%

Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer

Feng

Wong

et al. 2015

Gut

911

858

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“…Our previous work showed some important impairments in skeletal muscle in tumour‐bearing rats, which had increased chymotrypsin activity, representing enhancements of the ubiquitin–proteasome pathway . The present results likely suggest that the higher proteolytic activity (increased chymotrypsin activity) that is associated with higher cell activity (higher AP activity) in heart tissue could be responsible for the ECG failure that was observed only in group W. In our previous research, as also found here, the leucine‐rich diet also minimized the observed changes in those enzymes, even in the heart. Despite the presence of tumour, the LW group exhibited some improvements in cardiac tissue, with minimal damaging effects produced by tumour development, as confirmed by the significant diet interaction effect.…”

Section: Discussionmentioning

confidence: 99%

Nutritional leucine supplementation attenuates cardiac failure in tumour‐bearing cachectic animals

Toneto

Ramos

Salomão

et al. 2016

J cachexia sarcopenia muscle

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BackgroundThe condition known as cachexia presents in most patients with malignant tumours, leading to a poor quality of life and premature death. Although the cancer‐cachexia state primarily affects skeletal muscle, possible damage in the cardiac muscle remains to be better characterized and elucidated. Leucine, which is a branched chain amino acid, is very useful for preserving lean body mass. Thus, this amino acid has been studied as a coadjuvant therapy in cachectic cancer patients, but whether this treatment attenuates the effects of cachexia and improves cardiac function remains poorly understood. Therefore, using an experimental cancer‐cachexia model, we evaluated whether leucine supplementation ameliorates cachexia in the heart.MethodsMale Wistar rats were fed either a leucine‐rich or a normoprotein diet and implanted or not with subcutaneous Walker‐256 carcinoma. During the cachectic stage (approximately 21 days after tumour implantation), when the tumour mass was greater than 10% of body weight, the rats were subjected to an electrocardiogram analysis to evaluate the heart rate, QT‐c, and T wave amplitude. The myocardial tissues were assayed for proteolytic enzymes (chymotrypsin, alkaline phosphatase, cathepsin, and calpain), cardiomyopathy biomarkers (myeloperoxidase, tissue inhibitor of metalloproteinases, and total plasminogen activator inhibitor 1), and caspase‐8, ‐9, ‐3, and ‐7 activity.ResultsBoth groups of tumour‐bearing rats, especially the untreated group, had electrocardiography alterations that were suggestive of ischemia, dilated cardiomyopathy, and sudden death risk. Additionally, the rats in the untreated tumour‐bearing group but not their leucine‐supplemented littermates exhibited remarkable increases in chymotrypsin activity and all three heart failure biomarkers analysed, including an increase in caspase‐3 and ‐7 activity.ConclusionsOur data suggest that a leucine‐rich diet could modulate heart damage, cardiomyocyte proteolysis, and apoptosis driven by cancer‐cachexia. Further studies must be conducted to elucidate leucine's mechanisms of action, which potentially includes the modulation of the heart's inflammatory process.

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Leucine modulates the effect of Walker factor, a proteolysis-inducing factor-like protein from Walker tumours, on gene expression and cellular activity in C2C12 myotubes

Cited by 15 publications

References 58 publications

A Leucine-Rich Diet Modulates the Tumor-Induced Down-Regulation of the MAPK/ERK and PI3K/Akt/mTOR Signaling Pathways and Maintains the Expression of the Ubiquitin-Proteasome Pathway in the Placental Tissue of NMRI Mice1

A Leucine-Rich Diet Modulates the Tumor-Induced Down-Regulation of the MAPK/ERK and PI3K/Akt/mTOR Signaling Pathways and Maintains the Expression of the Ubiquitin-Proteasome Pathway in the Placental Tissue of NMRI Mice1

Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer

Nutritional leucine supplementation attenuates cardiac failure in tumour‐bearing cachectic animals

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