Humoral mediation for cachexia in tumour-bearing rats

Tessitore, Luciana; Costelli, Paola; Baccino, Francesco M.

doi:10.1038/bjc.1993.4

Cited by 109 publications

(81 citation statements)

References 75 publications

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“…Corticosterone was elevated (day 7) and insulin decreased (days 4 and 7) in the blood plasma of AH-130 hosts at day 7, as previously observed (Tessitore et al, 1993b). When these animals were administered IL-15, neither insulin nor corticosterone levels were significantly affected, suggesting that the effects of the cytokine were not mediated through these hormones.…”

Section: Resultssupporting

confidence: 78%

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Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats

et al. 2000

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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 by 14 C-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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Section: Resultssupporting

confidence: 78%

“…of tumour necrosis factor-α (TNF) and perturbations in hormonal homeostasis (Tessitore et al, 1993b) may play an important role in forcing metabolic balance towards the catabolic side.…”

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confidence: 99%

Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats

et al. 2000

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“…As a final remark, tumour necrosis factor (TNF) is an important mediator of cachexia in AH-130 tumour-bearing rats (Costelli et al, 1993;Tessitore et al, 1993a;Llovera et al, 1996) and in other situations. A reported effect of this cytokine, on some cell types at least, is to cause [Ca 2+ ] i elevations (Bick et al, 1997;Furukawa and Mattson, 1998), which, in the light of the present observations, might well have a role in activating the Ca 2+ -dependent proteolysis.…”

Section: Discussionmentioning

confidence: 99%

Activation of Ca2+-dependent proteolysis in skeletal muscle and heart in cancer cachexia

et al. 2001

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Cachexia is a syndrome characterized by profound tissue wasting that frequently complicates malignancies. In a cancer cachexia model we have shown that protein depletion in the skeletal muscle, which is a prominent feature of the syndrome, is mostly due to enhanced proteolysis. There is consensus on the views that the ubiquitin/proteasome pathway plays an important role in such metabolic response and that cytotoxic cytokines such as TNFα are involved in its triggering (Costelli and Baccino, 2000), yet the mechanisms by which the relevant extracellular signals are transduced into protein hypercatabolism are largely unknown. Moreover, little information is presently available as to the possible involvement in muscle protein waste of the Ca 2+ -dependent proteolysis, which may provide a rapidly activated system in response to the extracellular signals. In the present work we have evaluated the status of the Ca 2+ -dependent proteolytic system in the gastrocnemius muscle of AH-130 tumour-bearing rats by assaying the activity of calpain as well as the levels of calpastatin, the natural calpain inhibitor, and of the 130 kDa Ca 2+ -ATPase, both of which are known calpain substrates. After tumour transplantation, total calpastatin activity progressively declined, while total calpain activity remained unchanged, resulting in a progressively increasing unbalance in the calpain/calpastatin ratio. A decrease was also observed for the 130 kDa plasma membrane form of Ca 2+ -ATPase, while there was no change in the level of the 90 kDa sarcoplasmic Ca 2+ -ATPase, which is resistant to the action of calpain. Decreased levels of both calpastatin and 130 kDa Ca 2+ -ATPase have been also detected in the heart of the tumour-bearers. These observations strongly suggest that Ca 2+ -dependent proteolysis was activated in the skeletal muscle and heart of tumour-bearing animals and raise the possibility that such activation may play a role in sparking off the muscle protein hypercatabolic response that characterizes cancer cachexia. © 2001 Cancer Research Campaign http://www.bjcancer.com

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“…Inhibition of PGE2 synthesis decreased the tumour growth rates in studies in vivo and in vitro (19,20), attenuating many of the cachexia symptoms and increasing survival (21). Consequently, in this study it was sought to establish whether the inhibition of prostaglandin synthesis also attenuated or reversed the effects of tumour growth on the hepatic mitochondrial CPT system.…”

Section: Voi 44 No 1 1998mentioning

confidence: 99%

“…This eicosanoid is thought to mediate many of the effects of tumour necrosis factor (36,37). The use of PGE2 inhibitors for counteracting the effects of tumour growth has been the focus of several studies, which report decreases of tumour growth rate (23,38), of anorexia (39) and of increases in fat and lean body mass (20,40). The results presented here show that treatment with the prostaglandiu inhibitor was able to reverse the detrimental effects of cachexia on hepatic CPT II activity.…”

Section: Biochemistry and Molecular Biology Internationalmentioning

confidence: 99%

Carnitine palmitoyltransferase II activity is decreased in liver mitochondria of cachectic rats bearing the Walker 256 carcinosarcoma: Effect of indomethacin treatment

Seelaender¹,

Curi²,

Colquhoun³

et al. 1998

IUBMB Life

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Summary. The syndrome of cancer cachexia is accompanied by several alterations of lipid metabolism, especially that in the liver. In this study we have investigated a possible mechanism whereby the presence of the Walker 256 carcinosarcoma affects hepatic fatty acid oxidative capacity in tumour-bearing rats. Hepatic mitochondrial outer membrane carnitine palmitoyltransferase I (CPT I), generally accepted as the main site of regulation of fatty acid oxidation, was unaffected by the presence of the extra-hepatic tumour. However, mitochondrial inner-membrane carnitine palmitoyltransferase II (CPT II) activity was markedly decreased in mitochondria isolated from the liver of tumour-bearing rats. Immuno-detection by Western blotting using a CPT IIspecific antibody identified two bands (corresponding to Mr 69,000 and 54,000) in tumourbearing rats whereas only the normal-sized CPT II was present (at the expected Mr 69,000) in mitochondria from control rats. It is suggested that the emergence of the second, smaller protein may represent a catalytically less active protein that arises in vivo, since its appearance was not affected by the inclusion of proteolysis inhibitors in the mitochondrial preparation buffers. Treatment of the tumour-bearing rats with indomethacin, a prostaglandin (including PGE2) synthesis inhibitor, increased CPT II activity to levels even higher than those found in the control animals. It is suggested that PGE2 may play a role in the control of CPT II expression in the liver of tumour-bearing rats. Indomethacin treatment did not affect either of the two CPT activities of the mitochondria isolated from tumour tissue.

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Humoral mediation for cachexia in tumour-bearing rats

Cited by 109 publications

References 75 publications

Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats

Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats

Activation of Ca2+-dependent proteolysis in skeletal muscle and heart in cancer cachexia

Carnitine palmitoyltransferase II activity is decreased in liver mitochondria of cachectic rats bearing the Walker 256 carcinosarcoma: Effect of indomethacin treatment

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