MG132-mediated inhibition of the ubiquitin–proteasome pathway ameliorates cancer cachexia

Zhang, Liuping; Tang, Hua; Yao, Kangde; Li, Rui; Zheng, Yueyong; Wang, Qiang; Zhou, Xiaoyu; Jin, Liangbin

doi:10.1007/s00432-013-1412-6

Cited by 56 publications

(53 citation statements)

References 38 publications

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“…In contrast with the results shown in the present study, treatment with a different proteasome inhibitor, namely MG132, has been reported to attenuate body weight loss and muscle depletion in mice bearing the C26 colon adenocarcinoma . Such a discrepancy could rely on the fact that MG132 does not just inhibit proteasome, but also cathepsins and calpains .…”

Section: Discussioncontrasting

confidence: 99%

Effect of the specific proteasome inhibitor bortezomib on cancer‐related muscle wasting

Penna

Bonetto

Aversa

et al. 2015

J cachexia sarcopenia muscle

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BackgroundMuscle wasting, a prominent feature of cancer cachexia, is mainly caused by sustained protein hypercatabolism. The enhanced muscle protein degradation rates rely on the activity of different proteolytic systems, although the Adenosine triphosphate (ATP)‐ubiquitin‐proteasome‐dependent pathway and autophagy have been shown to play a pivotal role. Bortezomib is a potent reversible and selective proteasome and NF‐κB inhibitor approved for the clinical use, which has been shown to be effective in preventing muscle wasting in different catabolic conditions. The aim of the present study has been to investigate whether pharmacological inhibition of proteasome by bortezomib may prevent skeletal muscle wasting in experimental cancer cachexia.MethodsCancer cachexia was induced in rats by intraperitoneal injection of Yoshida AH‐130 ascites hepatoma cells and in mice by subcutaneous inoculation of C26 carcinoma cells. Animals were then further randomized to receive bortezomib. The AH‐130 hosts were weighted and sacrificed under anaesthesia, on Days 3, 4, 5, and 7 after tumour inoculation, while C26‐bearing mice were weighted and sacrificed under anaesthesia 12 days after tumour transplantation. NF‐κB and proteasome activation, MuRF1 and atrogin‐1 mRNA expression and beclin‐1 protein levels were evaluated in the gastrocnemius of controls and AH‐130 hosts.ResultsBortezomib administration in the AH‐130 hosts, although able to reduce proteasome and NF‐κB DNA‐binding activity in the skeletal muscle on Day 7 after tumour transplantation, did not prevent body weight loss and muscle wasting. In addition, bortezomib exerted a transient toxicity, as evidenced by the reduced food intake and by the increase in NF‐κB DNA‐binding activity in the AH‐130 hosts 3 days after tumour transplantation. Beclin‐1 protein levels were increased by bortezomib treatment in Day 3 controls but were unchanged on both Days 3 and 7 in the AH‐130 hosts, suggesting that an early compensatory induction of autophagy may exist in healthy but not in tumour‐bearing animals. Regarding C26‐bearing mice, bortezomib did not prevent as well body and muscle weight loss 12 days after tumour implantation.ConclusionsThe results obtained suggest that proteasome inhibition by bortezomib is not able to prevent muscle wasting in experimental cancer cachexia. Further studies are needed to address the issue whether a different dosage of bortezomib alone or in combination with other drugs modulating different molecular pathways may effectively prevent muscle wasting during cancer cachexia.

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Section: Discussioncontrasting

confidence: 99%

Effect of the specific proteasome inhibitor bortezomib on cancer‐related muscle wasting

Penna

Bonetto

Aversa

et al. 2015

J cachexia sarcopenia muscle

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“…Deletion of the TRAF6 reduced the expression of the muscle-specific ubiquitin ligases MuRF1 and MAFBx (18), which are critical proteins in the development of muscle atrophy (41,42). We further inferred that MAFBx and MuRF1 may be upregulated in denervated TA muscle.…”

Section: Discussionmentioning

confidence: 80%

Proteomic and bioinformatic analysis of differentially expressed proteins in denervated skeletal muscle

Sun

Qiu

Chen

et al. 2014

International Journal of Molecular Medicine

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Abstract. The aim of this study was to improve our understanding and the current treatment of denervation-induced skeletal muscle atrophy. We used isobaric tags for relative and absolute quantification (iTRAQ) coupled with two-dimensional liquid chromatography-tandem mass spectrometry (2D LC-MS/MS) to identify the differentially expressed proteins in the tibialis anterior (TA) muscle of rats at 1 and 4 weeks following sciatic nerve transection. A total of 110 proteins was differentially expressed and was further classified using terms from the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases to unravel their molecular functions. Among the differentially expressed metabolic enzymes involved in glycolysis, Krebs cycle and oxidative phosphorylation, α-and β-enolase displayed an increased and decreased expression, respectively, which was further validated by western blot analysis and immunohistochemistry. These findings suggest that the enolase isozymic switch during denervation-induced muscle atrophy is the reverse of that occurring during muscle maturation. Notably, protein-protein interaction analysis using the STRING database indicated that the protein expression of tumor necrosis factor receptor-associated factor-6 (TRAF6), muscle ring-finger protein 1 (MuRF1) and muscle atrophy F-box (MAFBx) was also upregulated during denervation-induced skeletal muscle atrophy, which was confirmed by western blot analysis. TRAF6 knockdown experiments in L6 myotubes suggested that the decreased expression of TRAF6 attenuated glucocorticoid-induced myotube atrophy. Therefore, we hypothesized that the upregulation of TRAF6 may be involved in the development of denervation-induced muscle atrophy, at least in part, by regulating the expression of MAFBx and MuRF1 proteins. The data from the present study provide valuable insight into the molecular mechanisms regulating denervation-induced muscle atrophy.

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“…These two E3 ubiquitin ligases have been heavily studied and regarded as a primary cause of wasting in cachexia. Treatment with the proteasome inhibitor MIG132 has been shown to alleviate cachexia by inhibiting MAFBx and MuRF-1, showing their involvement in wasting (44). The wasting phenotype does not involve a reduction in the total number of muscle fibers or altered force generation per unit of cross-sectional area (25,29), although others have reported a significant reduction of force/cross-sectional area in the murine C26 model (28) and in human patients (38).…”

Section: Discussionmentioning

confidence: 99%

Metalloproteinase expression is altered in cardiac and skeletal muscle in cancer cachexia

Devine

Bicer

Reiser

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Cardiac and skeletal muscle dysfunction is a recognized effect of cancerinduced cachexia, with alterations in heart function leading to heart failure and negatively impacting patient morbidity. Cachexia is a complex and multifaceted disease state with several potential contributors to cardiac and skeletal muscle dysfunction. Matrix metalloproteinases (MMPs) are a family of enzymes capable of degrading components of the extracellular matrix (ECM). Changes to the ECM cause disruption both in the connections between cells at the basement membrane and in cell-to-cell interactions. In the present study, we used a murine model of C26 adenocarcinoma-induced cancer cachexia to determine changes in MMP gene and protein expression in cardiac and skeletal muscle. We analyzed MMP-2, MMP-3, MMP-9, and MMP-14 as they have been shown to contribute to both cardiac and skeletal muscle ECM changes and, thereby, to pathology in models of heart failure and muscular dystrophy. In our model, cardiac and skeletal muscles showed a significant increase in RNA and protein levels of several MMPs and tissue inhibitors of metalloproteinases. Cardiac muscle showed significant protein increases in MMP-2, MMP-3, MMP-9, and MMP-14, whereas skeletal muscles showed increases in MMP-2, MMP-3, and MMP-14. Furthermore, collagen deposition was increased after C26 adenocarcinoma-induced cancer cachexia as indicated by an increased left ventricular picrosirius red-positive-stained area. Increases in serum hydroxyproline suggest increased collagen turnover, implicating skeletal muscle remodeling. Our findings demonstrate that cancer cachexia-associated matrix remodeling results in cardiac fibrosis and possible skeletal muscle remodeling. With these findings, MMPs represent a possible therapeutic target for the treatment of cancer-induced cachexia.

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MG132-mediated inhibition of the ubiquitin–proteasome pathway ameliorates cancer cachexia

Cited by 56 publications

References 38 publications

Effect of the specific proteasome inhibitor bortezomib on cancer‐related muscle wasting

Effect of the specific proteasome inhibitor bortezomib on cancer‐related muscle wasting

Proteomic and bioinformatic analysis of differentially expressed proteins in denervated skeletal muscle

Metalloproteinase expression is altered in cardiac and skeletal muscle in cancer cachexia

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