Abstract
A prominent feature of several type of cancer is cachexia. This syndrome causes a marked loss of lean body mass and muscle wasting, and appears to be mediated by cytokines and tumour products. There are several proteases and proteolytic pathways that could be responsible for the protein breakdown. In the present study, we investigated whether caspases are involved in the proteolytic process of skeletal muscle catabolism observed in a murine model of cancer cachexia (MAC16), in comparison with a related tumour (MAC13), which does not induce cachexia. Using specific peptide substrates, there was an increase of 54% in the proteolytic activity of caspase-1, 84% of caspase-8, 98% of caspase-3 151% to caspase-6 and 177% of caspase-9, in the gastrocnemius muscle of animals bearing the MAC16 tumour (up to 25% weight loss), in relation to muscle from animals bearing the MAC13 tumour (1–5% weight loss). The dual pattern of 89 kDa and 25 kDa fragmentation of poly (ADP-ribose) polymerase (PARP) occurred in the muscle samples from animals bearing the MAC16 tumour and with a high amount of caspase-like activity. Cytochrome c was present in the cytosolic fractions of gastrocnemius muscles from both groups of animals, suggesting that cytochrome c release from mitochondria may be involved in caspase activation. There was no evidence for DNA fragmentation into a nucleosomal ladder typical of apoptosis in the muscles of either group of mice. This data supports a role for caspases in the catabolic events in muscle involved in the cancer cachexia syndrome. © 2001 Cancer Research Campaign
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Adams JM and Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281: 1322–1326
Alnemri ES (1997) Mammalian cell death proteases: a family of highly conserved aspartate specific cysteine proteases. J Cell Biochem 64: 33–42
Ashkenazi A and Dixit VM (1998) Death receptors: signaling and modulation. Science 281: 1305–1308
Beck SA and Tisdale MJ (1987) Production of lipolytic and proteolytic factors by a murine-tumor-producing cachexia in the host. Cancer Res 47: 5919–5923
Bossy-Wetzel E and Green DR (1999) Caspases induce cytochrome c release from mitochondria by activating cytosolic factors. J Biol Chem 274: 17484–17490
Bradford M (1976) A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254
Cryns V and Yuan J (1998) Proteases to die for. Genes and Develop 12: 1551–1570
Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG and Earnshaw WC (1994) Cleavage of poly (ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 371: 346–347
Lecker SH, Solomon V, Mitch WE and Goldberg AL (1999) Muscle protein breakdown and the critical role of the ubiquitin-proteasome pathway in normal and disease states. J Nutr 129: 227S–237S
Libera LD, Zennaro R, Sandri M, Ambrosio GB and Vescovo G (1999) Apoptosis and atrophy in rat slow skeletal muscle in chronic heart failure. Am J Physiol 277: C982–C986
Livingston DJ (1997) in vitro and in vivo studies of ICE inhibitors. J Cell Biochem 64: 19–26
Lorite MJ, Cariuk P and Tisdale MJ (1997) Induction of muscle protein degradation by a tumour factor. Br J Cancer 76: 1035–1040
Lorite MJ, Thompson MG, Drake JL, Carling G and Tisdale MJ (1998) Mechanism of muscle protein degradation induced by a cancer cachectic factor. Br J Cancer 78: 850–856
Mignotte B and Vayassiere J-L (1998) Mitochondria and apoptosis. Eur J Biochem 252: 1–15
Miossec C, Dutilleul V, Fassy F and Diu-Hercend A (1997) Evidence for CPP32 activation in the absence of apoptosis during T lymphocytes stimulation. J Biol Chem 272: 13459–13462
Narula J, Pandey P, Arbustin E, Haider N, Narula N, Kolodgie FD, Bello BD, Semigran MJ, Bielsa-Masdeu A and Dec GW (1999) Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy. Proc Natl Acad Sci USA 96: 8144–8149
Nicholson DW and Thornberry NA (1997) Caspases: killer proteases. TIBS 22: 299–306
Pieper A, Verma A, Zhang J and Snyder SH (1999) Poly (ADP-ribose) polymerase, nitric oxide and cell death. TIPS 20: 171–181
Reed JC and Paternostro G (1999) Postmitochondrial regulation of apoptosis during heart failure. Proc Natl Acad Sci USA 96: 7614–7616
Sandri M, Carraro U, Okolov MP, Rizzi C, Arslan P, Monti D and Franceschi C (1995) Apoptosis, DNA damage and ubiquitin expression in normal and mdx muscle fibres after exercise. FEBS Lett 373: 291–295
Smith KL and Tisdale MJ (1993) Increased protein degradation and decreased protein synthesis in skeletal muscle during cancer cachexia. Br J Cancer 67: 680–685
Thornberry NA (1994) Interleukin-1β converting enzyme. Meth Enzymol 244: 615–631
Thornberry NA and Lazebnik Y (1998) Caspases: enemies within. Sciences 281: 1313–1316
Tilly JL, Kowalski KI, Johnson AI and Hsueh JW (1991) Involvement of apoptosis in ovarian follicular atresia a post-ovulatory regression. Endocrinology 129: 2799–2801
Tisdale M (1997) Biology of Cachexia. J Natl Cancer Inst 89: 1763–1773
Ushmorov A, Hack, and Droge W (1999) Differential reconstitution of mitochondrial respiratory chain activity and plasma redox state by cysteine and ornithine in a model of cancer cachexia. Cancer Res 59: 3527–3534
Van Royen M, Carbo N, Busquets S, Alvarez B, Quinn LS, Lopez-Soriano FJ and Argilés JM (2000) DNA fragmentation occurs in skeletal muscle during tumor growth: a link with cancer cachexia? Biochem Biophys Res Commun 270: 533–537
Villa P, Kaufmann SH and Earnshaw WC (1997) Caspases and caspase inhibitors. TIBS 22: 388–392
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Belizário, J., Lorite, M. & Tisdale, M. Cleavage of caspases-1, -3, -6, -8 and -9 substrates by proteases in skeletal muscles from mice undergoing cancer cachexia. Br J Cancer 84, 1135–1140 (2001). https://doi.org/10.1054/bjoc.2001.1700
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2001.1700
Keywords
This article is cited by
-
Cardiac Complications: The Understudied Aspect of Cancer Cachexia
Cardiovascular Toxicology (2022)
-
Protein and electrolyte contents and histopathology of longus colli muscle in cachexia of Red Bororo beef cows
Comparative Clinical Pathology (2021)
-
Immunohistochemical phenotyping of T cells, granulocytes, and phagocytes in the muscle of cancer patients: association with radiologically defined muscle mass and gene expression
Skeletal Muscle (2019)
-
Skeletal muscle wasting and renewal: a pivotal role of myokine IL-6
SpringerPlus (2016)
-
Serological muscle loss biomarkers: an overview of current concepts and future possibilities
Journal of Cachexia, Sarcopenia and Muscle (2013)