Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Apr;84(8):1135–1140. doi: 10.1054/bjoc.2001.1700

Cleavage of caspases-1, -3, -6, -8 and -9 substrates by proteases in skeletal muscles from mice undergoing cancer cachexia

J E Belizário 1, M J Lorite 2, M J Tisdale 2
PMCID: PMC2363854  PMID: 11308266

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 http://www.bjcancer.com

Keywords: cancer cachexia, muscle proteolysis, apoptosis, caspases

Full Text

The Full Text of this article is available as a PDF (461.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams J. M., Cory S. The Bcl-2 protein family: arbiters of cell survival. Science. 1998 Aug 28;281(5381):1322–1326. doi: 10.1126/science.281.5381.1322. [DOI] [PubMed] [Google Scholar]
  2. Alnemri E. S. Mammalian cell death proteases: a family of highly conserved aspartate specific cysteine proteases. J Cell Biochem. 1997 Jan;64(1):33–42. doi: 10.1002/(sici)1097-4644(199701)64:1<33::aid-jcb6>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
  3. Ashkenazi A., Dixit V. M. Death receptors: signaling and modulation. Science. 1998 Aug 28;281(5381):1305–1308. doi: 10.1126/science.281.5381.1305. [DOI] [PubMed] [Google Scholar]
  4. Beck S. A., Tisdale M. J. Production of lipolytic and proteolytic factors by a murine tumor-producing cachexia in the host. Cancer Res. 1987 Nov 15;47(22):5919–5923. [PubMed] [Google Scholar]
  5. Bossy-Wetzel E., Green D. R. Caspases induce cytochrome c release from mitochondria by activating cytosolic factors. J Biol Chem. 1999 Jun 18;274(25):17484–17490. doi: 10.1074/jbc.274.25.17484. [DOI] [PubMed] [Google Scholar]
  6. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  7. Cryns V., Yuan J. Proteases to die for. Genes Dev. 1998 Jun 1;12(11):1551–1570. doi: 10.1101/gad.12.11.1551. [DOI] [PubMed] [Google Scholar]
  8. Lazebnik Y. A., Kaufmann S. H., Desnoyers S., Poirier G. G., Earnshaw W. C. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature. 1994 Sep 22;371(6495):346–347. doi: 10.1038/371346a0. [DOI] [PubMed] [Google Scholar]
  9. Lecker S. H., Solomon V., Mitch W. E., Goldberg A. L. Muscle protein breakdown and the critical role of the ubiquitin-proteasome pathway in normal and disease states. J Nutr. 1999 Jan;129(1S):227S–237S. doi: 10.1093/jn/129.1.227S. [DOI] [PubMed] [Google Scholar]
  10. Libera L. D., Zennaro R., Sandri M., Ambrosio G. B., Vescovo G. Apoptosis and atrophy in rat slow skeletal muscles in chronic heart failure. Am J Physiol. 1999 Nov;277(5 Pt 1):C982–C986. doi: 10.1152/ajpcell.1999.277.5.C982. [DOI] [PubMed] [Google Scholar]
  11. Livingston D. J. In vitro and in vivo studies of ICE inhibitors. J Cell Biochem. 1997 Jan;64(1):19–26. [PubMed] [Google Scholar]
  12. Lorite M. J., Cariuk P., Tisdale M. J. Induction of muscle protein degradation by a tumour factor. Br J Cancer. 1997;76(8):1035–1040. doi: 10.1038/bjc.1997.504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lorite M. J., Thompson M. G., Drake J. L., Carling G., Tisdale M. J. Mechanism of muscle protein degradation induced by a cancer cachectic factor. Br J Cancer. 1998 Oct;78(7):850–856. doi: 10.1038/bjc.1998.592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Mignotte B., Vayssiere J. L. Mitochondria and apoptosis. Eur J Biochem. 1998 Feb 15;252(1):1–15. doi: 10.1046/j.1432-1327.1998.2520001.x. [DOI] [PubMed] [Google Scholar]
  15. Miossec C., Dutilleul V., Fassy F., Diu-Hercend A. Evidence for CPP32 activation in the absence of apoptosis during T lymphocyte stimulation. J Biol Chem. 1997 May 23;272(21):13459–13462. doi: 10.1074/jbc.272.21.13459. [DOI] [PubMed] [Google Scholar]
  16. Narula J., Pandey P., Arbustini E., Haider N., Narula N., Kolodgie F. D., Dal Bello B., Semigran M. J., Bielsa-Masdeu A., Dec G. W. Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy. Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):8144–8149. doi: 10.1073/pnas.96.14.8144. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nicholson D. W., Thornberry N. A. Caspases: killer proteases. Trends Biochem Sci. 1997 Aug;22(8):299–306. doi: 10.1016/s0968-0004(97)01085-2. [DOI] [PubMed] [Google Scholar]
  18. Pieper A. A., Verma A., Zhang J., Snyder S. H. Poly (ADP-ribose) polymerase, nitric oxide and cell death. Trends Pharmacol Sci. 1999 Apr;20(4):171–181. doi: 10.1016/s0165-6147(99)01292-4. [DOI] [PubMed] [Google Scholar]
  19. Reed J. C., Paternostro G. Postmitochondrial regulation of apoptosis during heart failure. Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):7614–7616. doi: 10.1073/pnas.96.14.7614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sandri M., Carraro U., Podhorska-Okolov M., Rizzi C., Arslan P., Monti D., Franceschi C. Apoptosis, DNA damage and ubiquitin expression in normal and mdx muscle fibers after exercise. FEBS Lett. 1995 Oct 16;373(3):291–295. doi: 10.1016/0014-5793(95)00908-r. [DOI] [PubMed] [Google Scholar]
  21. Smith K. L., Tisdale M. J. Increased protein degradation and decreased protein synthesis in skeletal muscle during cancer cachexia. Br J Cancer. 1993 Apr;67(4):680–685. doi: 10.1038/bjc.1993.126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Thornberry N. A. Interleukin-1 beta converting enzyme. Methods Enzymol. 1994;244:615–631. doi: 10.1016/0076-6879(94)44045-x. [DOI] [PubMed] [Google Scholar]
  23. Thornberry N. A., Lazebnik Y. Caspases: enemies within. Science. 1998 Aug 28;281(5381):1312–1316. doi: 10.1126/science.281.5381.1312. [DOI] [PubMed] [Google Scholar]
  24. Tilly J. L., Kowalski K. I., Johnson A. L., Hsueh A. J. Involvement of apoptosis in ovarian follicular atresia and postovulatory regression. Endocrinology. 1991 Nov;129(5):2799–2801. doi: 10.1210/endo-129-5-2799. [DOI] [PubMed] [Google Scholar]
  25. Tisdale M. J. Biology of cachexia. J Natl Cancer Inst. 1997 Dec 3;89(23):1763–1773. doi: 10.1093/jnci/89.23.1763. [DOI] [PubMed] [Google Scholar]
  26. Ushmorov A., Hack V., Dröge W. Differential reconstitution of mitochondrial respiratory chain activity and plasma redox state by cysteine and ornithine in a model of cancer cachexia. Cancer Res. 1999 Jul 15;59(14):3527–3534. [PubMed] [Google Scholar]
  27. Villa P., Kaufmann S. H., Earnshaw W. C. Caspases and caspase inhibitors. Trends Biochem Sci. 1997 Oct;22(10):388–393. doi: 10.1016/s0968-0004(97)01107-9. [DOI] [PubMed] [Google Scholar]
  28. van Royen M., Carbó N., Busquets S., Alvarez B., Quinn L. S., López-Soriano F. J., Argilés J. M. DNA fragmentation occurs in skeletal muscle during tumor growth: A link with cancer cachexia? Biochem Biophys Res Commun. 2000 Apr 13;270(2):533–537. doi: 10.1006/bbrc.2000.2462. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES