Abstract
Tissue protein hypercatabolism (TPH) is an important feature in cancer cachexia, particularly with regard to the skeletal muscle. The Yoshida AH-130 rat ascites hepatoma is a model system for studying the mechanisms involved in the processes that lead to tissue depletion, since it induces in the host a rapid and progressive muscle wasting, primarily due to TPH. The present study was aimed at investigating if IL-15, which is known to favour muscle fibre hypertrophy, could antagonize the enhanced muscle protein breakdown in this cancer cachexia model. Indeed, IL-15 treatment partly inhibited skeletal muscle wasting in AH-130-bearing rats by decreasing (8-fold) protein degradative rates (as measured by14C-bicarbonate pre-loading of muscle proteins) to values even lower than those observed in non-tumour-bearing animals. These alterations in protein breakdown rates were associated with an inhibition of the ATP-ubiquitin-dependent proteolytic pathway (35% and 41% for 2.4 and 1.2 kb ubiquitin mRNA, and 57% for the C8 proteasome subunit, respectively). The cytokine did not modify the plasma levels of corticosterone and insulin in the tumour hosts. The present data give new insights into the mechanisms by which IL-15 exerts its preventive effect on muscle protein wasting and seem to warrant the implementation of experimental protocols involving the use of the cytokine in the treatment of pathological states characterized by TPH, particularly in skeletal muscle, such as in the present model of cancer cachexia. © 2000 Cancer Research Campaign
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References
Akbar AN, Borthwick NJ, Wickremashinge RG, Panayoitidis P, Pilling D, Bofill M, Krajewski S, Reed JC and Salmon M (1996) IL-2 receptor γ-chain signalling cytokines regulate activated T-cell apoptosis in response to growth factor withdrawal: selective induction of anti-apoptotic (bcl-2, bcl-XL) but not proapoptotic (bax, bcl-XS) gene expression. Eur J Immunol 26: 294–299
Albano JDM, Ekins RP, Maritz G and Turner RC (1972) A sensitive and precise radioimmunoassay of serum insulin. Acta Endocrinol 70: 487–509
Argilés JM and López-Soriano FJ (1996) The ubiquitin-dependent proteolytic pathway in skeletal muscle: its role in pathological states. Trends Pharmacol Sci 17: 223–226
Armitage RJ, Macduff BM, Eisenman J, Paxton R and Grabstein KH (1995) IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation. J Immunol 154: 483–490
Baccino FM, Tessitore L, Bonelli G and Isidoro C (1986) Protein turnover states of tumour cells and host tissues in an experimental model. Biomed Biochim Acta 45: 1585–1590
Beck SA and Tisdale MJ (1989) Nitrogen excretion in cancer cachexia and its modification by a high fat diet in mice. Cancer Res 49: 3800–3804
Beck SA, Smith KL and Tisdale MJ (1991) Anticachectic and antitumour effect of eicosapentaenoic acid and its effect on protein turnover. Cancer Res 51: 6089–6093
Bond U and Schlesinger MJ (1985) Ubiquitin is a heat-shock protein in chicken-embryo fibroblasts. Mol Cell Biol 5: 949–956
Bond U, Agell N, Haas AL, Redman K and Schlesinger MJ (1988) Ubiquitin in stressed chicken embryo fibroblasts. J Biol Chem 263: 2384–2388
Bradford MM (1976) A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle protein-dye binding. Anal Biochem 72: 248–254
Bruton JD, Bamford RN, Peters C, Grant AJ, Kurys G, Goldman CK, Brennan J, Roessler E and Waldmann TA (1994) A lymphokine, provisionally designated interleukin T and produced by a human adult T cell leukemia line, stimulates T cell proliferation and the induction of lymphokine-activated killer cells. Proc Natl Acad Sci USA 91: 4935–4939
Bulfone-Paus S, Ungureanu D, Pohl T, Lindner G, Paus R, Ruckert R, Krause H and Kunzendorf U (1997) Interleukin-15 protects from lethal apoptosis in vitro. Nature Med 3: 1124–1128
Carbó N, Costelli P, Tessitore L, Bagby GJ, López-Soriano FJ, Baccino FM and Argilés JM (1994) Anti-TNF treatment interferes with changes in lipid metabolism in a tumour cachexia model. Clin Sci 87: 349–355
Carbó N, López-Soriano J, Costelli P, Alvarez B, Busquets S, Baccino FM, Quinn LS, López-Soriano FJ and Argilés JM (2000). Interleukin-15 mediates reciprocal regulation of adipose tissue and muscle mass: a potential role in body weight control,
Carson WE, Giri JG, Lindemann MJ, Linett ML, Ahdieh M, Paxton R, Anderson D, Eisenman J, Grabstein K and Caligiuri MA (1994) Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J Exp Med 180: 1395–1403
Carson WE, Fehniger TA, Haldar S, Eckhert K, Lindemann MJ, Lai CF, Croce CM, Baumann H and Caligiuri MA (1997) A potential role for interleukin-15 in the regulation of human natural killer cell survival. J Clin Invest 99: 937–943
Chomczynski P and Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate phenol chloroform extraction. Anal Biochem 162: 156–159
Ciechanover A, Finley D and Varshavsky A (1984) Ubiquitin dependence of selective protein degradation demonstrated in the mammalian cell cycle mutant ts85. Cell 37: 57–66
Costelli P, Carbó N, Tessitore L, Bagby GJ, López-Soriano FJ, Argilés JM and Baccino FM (1993) Tumour necrosis factor-α mediates changes in protein turnover in a rat cancer cachexia model. J Clin Invest 92: 2783–2789
Costelli P, García-Martínez C, Llovera M, Carbó N, López-Soriano FJ, Agell N, Tessitore L, Baccino FM and Argilés JM (1995) Muscle protein waste in tumor-bearing rats is effectively antagonized by a β2-adrenergic agonist (clenbuterol). J Clin Invest 95: 2367–2372
Dessì S, Batetta B, Anchisi C, Pani P, Costelli P, Tessitore L and Baccino FM (1992) Cholesterol metabolism during the growth of a rat ascites hepatoma (Yoshida AH-130). Br J Cancer 66: 787–793
Emery PW, Neville AM, Edwards RHT and Rennie MJ (1982) Increased myofibrillar degradation and decreased protein synthesis in tumor-bearing mice. Eur J Clin Invest 12: 10
García-Martínez C, López-Soriano FJ and Argilés JM (1993) Acute treatment with tumour necrosis factor-α induces changes in protein metabolism in rat skeletal muscle. Mol Cell Biochem 125: 11–18
Garlick PJ, Millward DJ, James WPT and Waterlow JC (1975) The effect of protein deprivation and starvation on the rate of protein synthesis in tissues of the rat. Biochim Biophys Acta 414: 71–84
Girard D, Paquet ME, Paquin R and Beaulieu AD (1996) Differential effects of interleukin-15 (IL-15) and IL-2 on human neutrophils: modulation of phagocytosis, cytoskeleton rearrangement, gene expression, and apoptosis by IL-15. Blood 88: 3176–3184
Giri JG, Ahdieh M, Eisenman J, Shanebeck K, Grabstein K, Kumaki S, Namen A, Park LS, Cosman D and Anderson D (1994) Utilization of the β and γ chain of the IL-2 receptor by the novel cytokine IL-15. EMBO J 13: 2822–2830
Grabstein KH, Eisenman J, Shanebeck K, Rauch C, Srinivasan S, Fung V, Beers C, Richardson J, Schoenborn MA, Ahdieh M, Johnson L, Alderson MR, Watson JD, Anderson DM and Giri JG (1994) Cloning of a T cell growth factor that interacts with the β chain of the interleukin-2 receptor. Science 264: 965–968
Hilenski LL, Terracio L, Haas AL and Borg TK (1992) Immunolocalization of ubiquitin conjugates at Z-bands and intercalated discs of rat cardiomyocytes in vitro and in vitro. J Histochem Cytochem 40: 1037–1042
Kien CL and Camitta BM (1983) Increased whole-body protein turnover in children with newly diagnosed leukemia or lymphoma. Cancer Res 43: 5592–5596
Kien CL and Camitta BM (1987) Close association of accelerated rates of whole body protein turnover (synthesis and breakdown) and energy expenditure in children with newly diagnosed acute lymphocytic leukaemia. J Parent Enteral Nutr 11: 129–134
Lawson DH, Richmond A, Nixon DW and Rudman D (1982) Metabolic approaches to cancer cachexia. Annu Rev Nutr 2: 277–301
Llovera M, López-Soriano FJ and Argilés JM (1993 a) Effects of tumour necrosis factor-α on muscle protein turnover in vitro in female rats. J Natl Cancer Inst 85: 1334–1339
Llovera M, López-Soriano FJ and Argilés JM (1993 b) Chronic tumour necrosis factor-α treatment modifies protein turnover in rat tissues. Biochem Mol Biol Int 30: 29–36
Llovera M, García-Martínez C, Agell N, Marzábal M, López-Soriano FJ and Argilés JM (1994) Ubiquitin gene expression is increased in skeletal muscle of tumour-bearing rats. FEBS Lett 338: 311–318
Llovera M, Garcia-Martínez C, Agell N, López-Soriano FJ and Argilés JM (1995) Muscle wasting associated with cancer cachexia is linked to an important activation of the ATP-dependent ubiquitin-mediated proteolysis. Int J Cancer 61: 138–141
Lowell BB, Ruderman NB and Goodman MN (1986) Evidence that lysosomes are not involved in the degradation of myofibrillar proteins in rat skeletal muscle. Biochem J 234: 237–240
Lundholm K, Ekman D, Edstrom S, Karlberg I, Jagenberg R and Scherstén T (1979) Protein synthesis in liver tissue under the influence of a methyl-cholanthrene-induced sarcoma in mice. Cancer Res 39: 4657–4661
Melville S, McNurlan MA, Graham Calder A and Garlick PJ (1990) Increased protein turnover despite normal energy metabolism and responses to feeding in patients with lung cancer. Cancer Res 50: 1125–1131
Moley JF, Morrison SD, Gorschboth CM and Norton JA (1988) Body composition changes in rats with experimental cancer cachexia: improvement with exogenous insulin. Cancer Res 48: 2784–2787
Morrison SD (1989) Cancer cachexia. In Influence of Tumor Development on the Host, (Liotta AL ed), pp. 176–213, Kluwer Academic Publ.: The Netherlands
Munger W, DeJoy SQ, Jeyaseelan R Sr, Torley LW, Grabstein KH, Eisenman J, Paxton R, Cox T, Wick MM and Kerwar SS (1995) Studies evaluating the antitumor activity and toxicity of interleukin-15, a new T cell growth factor: comparison with interleukin-2. Cell Immunol 165: 289–293
Pain VM, Randall DP and Garlick PJ (1984) Protein synthesis in liver and skeletal muscle of mice bearing an ascites tumor. Cancer Res 44: 1054–1057
Popp MB, Wagner SC, Enrione EB and Brito OJ (1988) Host and tumor responses to varying rates of nitrogen infusion in the tumor-bearing rat. Ann Surg 207: 80–89
Quinn LS, Haugk KL and Grabstein KH (1995) Interleukin-15: a novel anabolic cytokine for skeletal muscle. Endocrinology 136: 3669–3672
Reinecker HC, MacDermott RP, Mirau S, Dignass A and Podolsky DK (1996) Intestinal epithelial cells both express and respond to interleukin-15. Gastroenterology 111: 1706–1713
Shaw JH and Wolfe RR (1988) Whole-body protein kinetics in patients with early and advanced gastrointestinal cancer: the early response to glucose infusion and total parenteral nutrition. Surgery 103: 148–155
Tanaka K, Kanamaya H, Tamura T, Lee DH, Kumatori A, Fujiwara T, Ichihara A, Tokunaga F, Aruga R and Iwanaga S (1990) cDNA cloning and sequencing of component C8 of proteasomes from rat hepatoma cells. Biochem Biophys Res Commun 171: 676–683
Tayek JA, Istfan NW, Jones CT, Hamawy KJ, Bistrian BR and Blackburn GL (1986) Influence of the Walker 256 carcinosarcoma on muscle, tumor, and whole-body protein synthesis and growth rate in the cancer-bearing rat. Cancer Res 46: 5649–5654
Tessitore L, Bonelli G, Isidoro C, Kazakova OV and Baccino FM (1986) Comparative studies of protein turnover regulations in tumor cells and host tissues: development and analysis of an experimental model. Toxicol Pathol 14: 451–456
Tessitore L, Bonelli G and Baccino FM (1987 a) Early development of protein metabolic perturbations in the liver and skeletal muscle of tumour-bearing rats. Biochem J 241: 153–159
Tessitore L, Bonelli G, Cecchini G, Amenta JS and Baccino FM (1987 b) Regulation of protein turnover versus growth state: ascites hepatoma as a model for studies both in the animal and in vitro. Arch Biochem Biophys 255: 372–384
Tessitore L, Costelli P, Bonetti G and Baccino FM (1993 a) Cancer cachexia, malnutrition, and tissue protein turnover in experimental animals. Arch Biochem Biophys 306: 52–58
Tessitore L, Costelli P and Baccino FM (1993 b) Humoral mediation for cancer cachexia in tumour-bearing rats. Br J Cancer 67: 15–23
Tessitore L, Costelli P and Baccino FM (1994) Pharmacological interference with tissue hypercatabolism in tumour-bearing rats. Biochem J 299: 71–78
Tisdale MJ (1992) Cancer cachexia. Br J Cancer 63: 337–342
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Carbó, N., López-Soriano, J., Costelli, P. et al. Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats. Br J Cancer 83, 526–531 (2000). https://doi.org/10.1054/bjoc.2000.1299
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DOI: https://doi.org/10.1054/bjoc.2000.1299
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