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. 1991 May;63(5):705–710. doi: 10.1038/bjc.1991.159

Bioactivity of skeletal muscle proteolysis-inducing factors in the plasma proteins from cancer patients with weight loss.

J E Belizario 1, M Katz 1, E Chenker 1, I Raw 1
PMCID: PMC1972408  PMID: 2039696

Abstract

We determined the circulating level of bioactivity for skeletal muscle proteolysis-inducing factors (PIF) in the blood samples from cancer patients whose body weight loss was greater than 10%. The level of bioactivity was estimated by measurement of tyrosine release from isolated 1at diaphragm muscles incubated with an ultrafiltered fraction of plasma or serum proteins containing molecules from 0 to 25 kDa in molecular weight. Significant levels of bioactivity were detected in 25 of the 50 cancer samples. No activity was found in 18 of the samples from healthy human blood donors. The ability of 13 of the cancer samples to induce muscle proteolysis was significantly inhibited by incubation of muscles in presence of indomethacin (10 microM). The neutralisation of 12 of the cancer samples with the antibodies to recombinant human interleukin-1 (IL-1), alpha and beta forms, partially abrogated the activity in five samples. These results suggest that the accelerated breakdown of proteins induced by the cancer plasma factors is at least in part mediated by IL-1 in cooperation with other active factors not yet defined. Additionally, we have shown that the increased breakdown of proteins induced by PIF in the crude supernatant derived from activated mouse peritoneal macrophages is prevented by the treatment of muscles with either indomethacin or quin-2 (1 microM). These observations provide indirect evidence for a possible causal relationship between the production of PIF and the body-weight loss of cancer patients.

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Selected References

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  1. Auron P. E., Webb A. C., Rosenwasser L. J., Mucci S. F., Rich A., Wolff S. M., Dinarello C. A. Nucleotide sequence of human monocyte interleukin 1 precursor cDNA. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7907–7911. doi: 10.1073/pnas.81.24.7907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baracos V. E., Goldberg A. L. Maintenance of normal length improves protein balance and energy status in isolated rat skeletal muscles. Am J Physiol. 1986 Oct;251(4 Pt 1):C588–C596. doi: 10.1152/ajpcell.1986.251.4.C588. [DOI] [PubMed] [Google Scholar]
  3. Baracos V., Greenberg R. E., Goldberg A. L. Influence of calcium and other divalent cations on protein turnover in rat skeletal muscle. Am J Physiol. 1986 Jun;250(6 Pt 1):E702–E710. doi: 10.1152/ajpendo.1986.250.6.E702. [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. Beutler B., Cerami A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature. 1986 Apr 17;320(6063):584–588. doi: 10.1038/320584a0. [DOI] [PubMed] [Google Scholar]
  6. Charters Y., Grimble R. F. Effect of recombinant human tumour necrosis factor alpha on protein synthesis in liver, skeletal muscle and skin of rats. Biochem J. 1989 Mar 1;258(2):493–497. doi: 10.1042/bj2580493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Clowes G. H., Jr, George B. C., Villee C. A., Jr, Saravis C. A. Muscle proteolysis induced by a circulating peptide in patients with sepsis or trauma. N Engl J Med. 1983 Mar 10;308(10):545–552. doi: 10.1056/NEJM198303103081001. [DOI] [PubMed] [Google Scholar]
  8. Dinarello C. A. Biology of interleukin 1. FASEB J. 1988 Feb;2(2):108–115. [PubMed] [Google Scholar]
  9. Dinarello C. A., Cannon J. G., Mier J. W., Bernheim H. A., LoPreste G., Lynn D. L., Love R. N., Webb A. C., Auron P. E., Reuben R. C. Multiple biological activities of human recombinant interleukin 1. J Clin Invest. 1986 Jun;77(6):1734–1739. doi: 10.1172/JCI112495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dinarello C. A., Cannon J. G., Wolff S. M., Bernheim H. A., Beutler B., Cerami A., Figari I. S., Palladino M. A., Jr, O'Connor J. V. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med. 1986 Jun 1;163(6):1433–1450. doi: 10.1084/jem.163.6.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dinarello C. A., Clowes G. H., Jr, Gordon A. H., Saravis C. A., Wolff S. M. Cleavage of human interleukin 1: isolation of a peptide fragment from plasma of febrile humans and activated monocytes. J Immunol. 1984 Sep;133(3):1332–1338. [PubMed] [Google Scholar]
  12. Endres S., Ghorbani R., Lonnemann G., van der Meer J. W., Dinarello C. A. Measurement of immunoreactive interleukin-1 beta from human mononuclear cells: optimization of recovery, intrasubject consistency, and comparison with interleukin-1 alpha and tumor necrosis factor. Clin Immunol Immunopathol. 1988 Dec;49(3):424–438. doi: 10.1016/0090-1229(88)90130-4. [DOI] [PubMed] [Google Scholar]
  13. Flick D. A., Gifford G. E. Comparison of in vitro cell cytotoxic assays for tumor necrosis factor. J Immunol Methods. 1984 Mar 30;68(1-2):167–175. doi: 10.1016/0022-1759(84)90147-9. [DOI] [PubMed] [Google Scholar]
  14. Flores E. A., Bistrian B. R., Pomposelli J. J., Dinarello C. A., Blackburn G. L., Istfan N. W. Infusion of tumor necrosis factor/cachectin promotes muscle catabolism in the rat. A synergistic effect with interleukin 1. J Clin Invest. 1989 May;83(5):1614–1622. doi: 10.1172/JCI114059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fong Y., Moldawer L. L., Marano M., Wei H., Barber A., Manogue K., Tracey K. J., Kuo G., Fischman D. A., Cerami A. Cachectin/TNF or IL-1 alpha induces cachexia with redistribution of body proteins. Am J Physiol. 1989 Mar;256(3 Pt 2):R659–R665. doi: 10.1152/ajpregu.1989.256.3.R659. [DOI] [PubMed] [Google Scholar]
  16. Fulks R. M., Li J. B., Goldberg A. L. Effects of insulin, glucose, and amino acids on protein turnover in rat diaphragm. J Biol Chem. 1975 Jan 10;250(1):290–298. [PubMed] [Google Scholar]
  17. Goldberg A. L., Kettelhut I. C., Furuno K., Fagan J. M., Baracos V. Activation of protein breakdown and prostaglandin E2 production in rat skeletal muscle in fever is signaled by a macrophage product distinct from interleukin 1 or other known monokines. J Clin Invest. 1988 May;81(5):1378–1383. doi: 10.1172/JCI113466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gubler U., Chua A. O., Stern A. S., Hellmann C. P., Vitek M. P., DeChiara T. M., Benjamin W. R., Collier K. J., Dukovich M., Familletti P. C. Recombinant human interleukin 1 alpha: purification and biological characterization. J Immunol. 1986 Apr 1;136(7):2492–2497. [PubMed] [Google Scholar]
  19. Hellerstein M. K., Meydani S. N., Meydani M., Wu K., Dinarello C. A. Interleukin-1-induced anorexia in the rat. Influence of prostaglandins. J Clin Invest. 1989 Jul;84(1):228–235. doi: 10.1172/JCI114145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Henderson-Smart D. J., Pettigrew A. G., Campbell D. J. Clinical apnea and brain-stem neural function in preterm infants. N Engl J Med. 1983 Feb 17;308(7):353–357. doi: 10.1056/NEJM198302173080702. [DOI] [PubMed] [Google Scholar]
  21. Kawakami M., Cerami A. Studies of endotoxin-induced decrease in lipoprotein lipase activity. J Exp Med. 1981 Sep 1;154(3):631–639. doi: 10.1084/jem.154.3.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kettelhut I. C., Goldberg A. L. Tumor necrosis factor can induce fever in rats without activating protein breakdown in muscle or lipolysis in adipose tissue. J Clin Invest. 1988 May;81(5):1384–1389. doi: 10.1172/JCI113467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Last-Barney K., Homon C. A., Faanes R. B., Merluzzi V. J. Synergistic and overlapping activities of tumor necrosis factor-alpha and IL-1. J Immunol. 1988 Jul 15;141(2):527–530. [PubMed] [Google Scholar]
  24. Lawson D. H., Richmond A., Nixon D. W., Rudman D. Metabolic approaches to cancer cachexia. Annu Rev Nutr. 1982;2:277–301. doi: 10.1146/annurev.nu.02.070182.001425. [DOI] [PubMed] [Google Scholar]
  25. Lundholm K., Karlberg I., Ekman L., Edström S., Scherstén T. Evaluation of anorexia as the cause of altered protein synthesis in skeletal muscles from nongrowing mice with sarcoma. Cancer Res. 1981 May;41(5):1989–1996. [PubMed] [Google Scholar]
  26. Mahony S. M., Beck S. A., Tisdale M. J. Comparison of weight loss induced by recombinant tumour necrosis factor with that produced by a cachexia-inducing tumour. Br J Cancer. 1988 Apr;57(4):385–389. doi: 10.1038/bjc.1988.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Mahony S. M., Tisdale M. J. Induction of weight loss and metabolic alterations by human recombinant tumour necrosis factor. Br J Cancer. 1988 Sep;58(3):345–349. doi: 10.1038/bjc.1988.216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Michie H. R., Manogue K. R., Spriggs D. R., Revhaug A., O'Dwyer S., Dinarello C. A., Cerami A., Wolff S. M., Wilmore D. W. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med. 1988 Jun 9;318(23):1481–1486. doi: 10.1056/NEJM198806093182301. [DOI] [PubMed] [Google Scholar]
  29. Moldawer L. L., Drott C., Lundholm K. Monocytic production and plasma bioactivities of interleukin-1 and tumour necrosis factor in human cancer. Eur J Clin Invest. 1988 Oct;18(5):486–492. doi: 10.1111/j.1365-2362.1988.tb01044.x. [DOI] [PubMed] [Google Scholar]
  30. Moldawer L. L., Svaninger G., Gelin J., Lundholm K. G. Interleukin 1 and tumor necrosis factor do not regulate protein balance in skeletal muscle. Am J Physiol. 1987 Dec;253(6 Pt 1):C766–C773. doi: 10.1152/ajpcell.1987.253.6.C766. [DOI] [PubMed] [Google Scholar]
  31. Norton J. A., Moley J. F., Green M. V., Carson R. E., Morrison S. D. Parabiotic transfer of cancer anorexia/cachexia in male rats. Cancer Res. 1985 Nov;45(11 Pt 1):5547–5552. [PubMed] [Google Scholar]
  32. Oliff A., Defeo-Jones D., Boyer M., Martinez D., Kiefer D., Vuocolo G., Wolfe A., Socher S. H. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell. 1987 Aug 14;50(4):555–563. doi: 10.1016/0092-8674(87)90028-6. [DOI] [PubMed] [Google Scholar]
  33. Pontremoli S., Melloni E. Extralysosomal protein degradation. Annu Rev Biochem. 1986;55:455–481. doi: 10.1146/annurev.bi.55.070186.002323. [DOI] [PubMed] [Google Scholar]
  34. Rodemann H. P., Goldberg A. L. Arachidonic acid, prostaglandin E2 and F2 alpha influence rates of protein turnover in skeletal and cardiac muscle. J Biol Chem. 1982 Feb 25;257(4):1632–1638. [PubMed] [Google Scholar]
  35. Rofe A. M., Conyers R. A., Bais R., Gamble J. R., Vadas M. A. The effects of recombinant tumour necrosis factor (cachectin) on metabolism in isolated rat adipocyte, hepatocyte and muscle preparations. Biochem J. 1987 Nov 1;247(3):789–792. doi: 10.1042/bj2470789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Semb H., Peterson J., Tavernier J., Olivecrona T. Multiple effects of tumor necrosis factor on lipoprotein lipase in vivo. J Biol Chem. 1987 Jun 15;262(17):8390–8394. [PubMed] [Google Scholar]
  37. Spriggs D., Imamura K., Rodriguez C., Horiguchi J., Kufe D. W. Induction of tumor necrosis factor expression and resistance in a human breast tumor cell line. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6563–6566. doi: 10.1073/pnas.84.18.6563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Stovroff M. C., Fraker D. L., Swedenborg J. A., Norton J. A. Cachectin/tumor necrosis factor: a possible mediator of cancer anorexia in the rat. Cancer Res. 1988 Aug 15;48(16):4567–4572. [PubMed] [Google Scholar]
  39. Theologides A. Cancer cachexia. Cancer. 1979 May;43(5 Suppl):2004–2012. doi: 10.1002/1097-0142(197905)43:5+<2004::aid-cncr2820430708>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  40. Tracey K. J., Wei H., Manogue K. R., Fong Y., Hesse D. G., Nguyen H. T., Kuo G. C., Beutler B., Cotran R. S., Cerami A. Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation. J Exp Med. 1988 Mar 1;167(3):1211–1227. doi: 10.1084/jem.167.3.1211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. WAALKES T. P., UDENFRIEND S. A fluorometric method for the estimation of tyrosine in plasma and tissues. J Lab Clin Med. 1957 Nov;50(5):733–736. [PubMed] [Google Scholar]
  42. Wallach D., Holtmann H., Engelmann H., Nophar Y. Sensitization and desensitization to lethal effects of tumor necrosis factor and IL-1. J Immunol. 1988 May 1;140(9):2994–2999. [PubMed] [Google Scholar]
  43. Warren R. S., Starnes H. F., Jr, Gabrilove J. L., Oettgen H. F., Brennan M. F. The acute metabolic effects of tumor necrosis factor administration in humans. Arch Surg. 1987 Dec;122(12):1396–1400. doi: 10.1001/archsurg.1987.01400240042007. [DOI] [PubMed] [Google Scholar]

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