Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In view of the postulated role of cathepsin D in cachexia, investigations have been pursued on the host tissue response of cathepsin D activity in DBA/2 mice inoculated with 5 X 10(5) L1210 tumor cells. The results confirmed previous investigators' findings of the increase in cathepsin D activity (specific activity) in liver and muscle of tumor bearers. In addition, it was found that this increase was a general response of the host since heart, kidney, lung, and spleen cathepsin D specific activity were also enhanced in tumor bearers. These increases ranged from an average of 10% for spleen to 100% for gastrocnemius muscle. This effect was age related in heart and kidney. As a working hypothesis, we propose the concept that tumor bearers release protease-enhancing factor(s) which trigger increase or enhancement of cathepsin D activity in host tissues by yet unknown mechanisms. Pepstatin (60 mg/kg), a known inhibitor of cathepsin D in vitro, was shown to provide long-lasting inhibition (3 to 6 days) of cathepsin D in vivo in non-tumor bearers particularly in spleen, liver, kidney, lung, and heart. Evidence is provided from assays of cell fractions that this inhibition takes place at or in the lysosome. The duration of the effectiveness of pepstatin was altered in tumor bearers in that cathepsin D activity of heart, lung, and spleen had returned to near normal values in 48 hr following pepstatin injection. However, in muscle, liver, and kidney, significant inhibition (90%) still persisted in tumor bearers as it did in non-tumor bearers. Pepstatin or related antiproteases may prove useful as "anticachexia" agents by decreasing proteolysis in muscle and other tissues.
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PMID:Host cathepsin D response to tumor in the normal and pepstatin-treated mouse. 685 May 78

The role of malnutrition in the development of cachexia in rats bearing the Yoshida ascites hepatoma AH-130 was investigated by comparing the changes in tissue protein turnover in these animals with those observed in pair-fed controls. The tumor elicited in rats an early and conspicuous loss of body weight and tissue waste. Protein loss was particularly prominent for the gastrocnemius muscle and the heart and less pronounced for the soleus, while the diaphragm was little affected. Liver, kidneys, and spleen transiently increased in weight then regressed and eventually atrophied, while adrenals were enlarged over the whole experimental period. Protein waste was mainly due to acceleration of tissue protein breakdown, this protein hypercatabolic state being associated with increased cathepsin D activity in liver and gastrocnemius. In pair-fed animals the liver showed a marked protein loss resulting from enhanced catabolism, while the sharp decrease of heart protein content and the less prominent waste of the gastrocnemius were due to a reduction in protein synthesis. The total plasmatic concentration of free amino acids in AH-130-bearing rats was decreased at Day 4, when the tumor was actively proliferating, and returned to control values at Day 10, when the tumor had reached a stationary state. On the contrary, in pair-fed animals total plasma amino acids decreased over the whole experimental period. Plasma branched-chain amino acids were unchanged or even decreased in tumor hosts, while the Gly/Pro ratio was elevated in pair-fed rats. The intracellular concentration of free amino acids was higher in stationary than in exponentially- growing tumors, reflecting the enhanced proteolytic rates observed in stationary tumor cells. On the whole, the results suggest that reduced food uptake and metabolic competition by the tumor are not sufficient to justify the marked hypercatabolism in host tissues during the AH-130 hepatoma growth. The profound differences between tumor-bearing and pair-fed animals suggest that, if malnutrition undoubtedly played a role in this model of cancer cachexia, its effects were overwhelmed and subverted in the frame of the tumor-host interplay that dictated a distinctively peculiar syndrome.
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PMID:Cancer cachexia, malnutrition, and tissue protein turnover in experimental animals. 821 20

The relationship between skeletal muscle aspartyl protease activity (APA) and wasting was investigated in male DBA/2 mice inoculated with L1210 tumor cells. Using the peptidic substrate H-Pro-Thr-Glu-Phe-Phe(NO2)-Arg-Leu-OH, which is specific for aspartyl proteases, proteases, proteolytic activity was detected in a number of tissues including muscle by using a crude extraction procedure for isolation of lysosomal enzymes. Biochemical characterization and increased muscle levels following either fasting or injection of endotoxin (ETX) suggest that the enzyme is likely cathepsin D. The wasting syndrome accompanying the tumor was measured by comparing the weight of the skinned hind limb in treated and control animals. DBA/2 mice inoculated intraperitoneally with L1210 cells developed multiple solid tumors in the peritoneum and ascites; maximal tumor burden was reached by 16 days. There was a significant reduction in hind limb weight (16 +/- 2%; mean +/- SE) and significant increase (31 +/- 8%) in muscle APA associated with the development of ascites and solid tumors. Plasma APA activity was substantially increased (240 +/- 33%), while liver and spleen APA were increased (10-20%) but not significantly. Chronic pepstatin administration, 30 mg.kg-1.day-1, for 7 days concurrent with the initiation of observable ascites and solid tumor formation (7 days post-inoculation), completely inhibited hind limb weight loss and alleviated the tumor-dependent increase of APA in both plasma and muscle without altering tumor development. Delaying the administration of pepstatin by 3 days resulted in less of an inhibition (33 +/- 13%) of hind limb weight loss. Thus, cathepsin D or a similar aspartyl protease appears to be of key importance in the wasting syndrome associated with cachexia.
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PMID:Muscle aspartyl protease (cathepsin D) activity: detection using a chromophoric substrate and relation to wasting in DBA/2 mice implanted with leukemic L1210 tumor cells. 902 34

Muscle wasting is a common and prominent feature of advanced cancer, including lung cancer. Evidence from animal experiments suggests that accelerated proteolysis via the ubiquitin--proteasome pathway is the primary cause of cancer-related cachexia. However, there are few data on the role of this pathway in determining muscle wasting in human cancer. The present study was designed to measure whether skeletal muscle gene expression of components of the ubiquitin-proteasome pathway and/or the lysosomal proteolytic pathway was increased in patients with early lung cancer. A total of 36 patients with lung cancer referred for curative resection and 10 control subjects had biopsies of latissimus dorsi muscle taken at operation. mRNA levels of four components of the ubiquitin-proteasome pathway, i.e. polyubiquitin, C2 alpha proteasome subunit, 14 kDa ubiquitin-carrier protein and ubiquitin-activating protein, and of two lysosomal proteolytic enzymes, i.e. cathepsin B and cathepsin D, were measured using quantitative Northern blotting. mRNA levels for cathepsin B, but not for components of the ubiquitin--proteasome pathway, were higher in patients with cancer compared with controls (P=0.01). Among lung cancer patients, cathepsin B mRNA levels correlated with fat-free mass index (r = -0.57, P=0.003) and tumour stage (r(s)=0.45, P=0.03), and were higher in smokers (P=0.04). Thus gene expression of the lysosomal protease cathepsin B is increased in the skeletal muscle of patients with early lung cancer, and the strong inverse relationship with fat-free mass suggests that cathepsin B may have a role in inducing muscle wasting in the early stages of lung cancer.
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PMID:Skeletal muscle mRNA levels for cathepsin B, but not components of the ubiquitin-proteasome pathway, are increased in patients with lung cancer referred for thoracotomy. 1186 77

Patients with cancer cachexia (CCX) suffer from muscle wasting, which is often but not always accompanied by selective loss of myosin. Here we examined the effects of CCX on muscle mass and myosin heavy chain (MyHC) expression in denervated (DEN) muscles, especially focusing on the protein synthesis and degradation pathways. Male CD2F1 mice were randomly divided into control (CNT) and CCX groups and their left sciatic nerve was transected. CCX was induced by an intraperitoneal injection of colon 26 cells. After 14 days, the serum concentration of IL-6 and corticosteroid was higher in CCX mice than in CNT mice. The combination of CCX with DEN (CCX + DEN) resulted in a marked reduction of the gastrocnemius muscle weight (-69%) that was significantly lower than DEN (-53%) or CCX (-36%) alone. CCX had no effect on MyHC content, but it elicited a preferential MyHC loss when combined with DEN. The expression levels of autophagy markers cathepsin D and LC3BII/I ratio were markedly higher in the CCX + DEN group than in the CNT + DEN and the CCX groups. Paradoxically, there was an increase in protein synthesis rate and phosphorylation levels of p70S6K and rpS6, markers of mTORC1 signaling, in the CNT + DEN group, and these molecular alterations were inhibited in the CCX + DEN group. Our data indicate that CCX aggravates muscle atrophy in DEN muscles by inducing seletive loss of myosin, which involves inactivity dependent mechanisms that is likely to be a consequence of increased autophagy-mediated protein breakdown coupled with impaired protein synthesis.
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PMID:Cancer Cachexia Induces Preferential Skeletal Muscle Myosin Loss When Combined With Denervation. 3242 14