The Role of the Ubiquitin Proteasome Pathway in Human Cancer Cachexia

Consistent with the observations in the experimental model, Williams et al. [21] demonstrated that mRNA levels for ubiquitin were approximately three times higher in rectus abdominis muscles from patients with miscellaneous cancers than in muscles from control patients. Moreover, the muscle mRNA levels for the 20s proteasome subunits were 300-400% higher than in healthy controls.

More recently, our group confirmed that the muscle ubiquitin/proteasome system is hyperacti-vated in humans bearing neoplastic diseases. Indeed, ubiquitin mRNA expression was markedly and significantly increased in muscle biopsies obtained preoperatively in 20 patients undergoing surgery for gastric cancer [22]. It is of interest that ubiquitin mRNA overexpression was observed even in patients reporting weight loss of < 5% of the usual body weight (Table 1). Moreover, patients with more advanced disease (i.e., in stage III-IV) had the highest ubiquitin mRNA values.

In a subsequent study [23], Bossola et al. evaluated proteasome-specific activities in intraoperative rectus abdominis muscle biopsies obtained from 23 patients undergoing laparotomy for gastric cancer and 14 controls undergoing laparotomy for benign abdominal diseases (Table 2). The authors showed that proteasome activity is significantly increased in the muscle of gastric cancer patients (five-fold increase in CTL activity, and a two-fold increase in PGP and TL activities). A concomitant, significant overexpression of muscle ubiquitin mRNA was also observed. Higher CTL activity was associated with advanced disease stage, weight loss, and hypoalbuminaemia, in keeping with the previous observation that muscle ubiquitin mRNA levels are influenced by tumour stage [22]. CTL activity was higher in cancer patients over 50 years old, though not in controls. This difference suggests that ageing may substantially alter the response to the catabolic stimuli

Table 1.Muscle ubiquitin m-RNA expression and weight loss in gastric cancer patients. (Data from [22])

Group

Ubiquitin m-RNA (arbitrary units ± SD)

Controls

1162 ± 132

Gastric cancer (weight loss 0-5%)

2338 ± 929a

Gastric cancer (weight loss 6-10%)

2581 ± 962a

Gastric cancer (weight loss > 10%)

2936 ± 756a

ap = 0.0005 vs controls

Table 2. Muscle proteasome chymotrypsin-like (CTL) activity and weight loss in gastric cancer patients. (Data from [23])

Group

Proteasome CTL activity (nkatal x 10 3/mg protein ± SD

Controls

67.5 ± 37.4

Gastric cancer (weight loss < 10%)

185.3 ± 112a

Gastric cancer (weight loss >1 0%)

621.6 ± 499b

ap < 0.0001 vs controls bp < 0.003 vs weight loss < 10%

ap < 0.0001 vs controls bp < 0.003 vs weight loss < 10%

evoked by the tumour.

Taken together, the results of the two latter clinical studies provide a number of interesting insights into the pathogenesis of muscle wasting in human cancer. First, they suggest a crucial involvement of the ATP-dependent ubiquitin/proteasome pathway in cancer-related muscle loss in humans. Second, the observation that both ubiquitin mRNA overexpression and increased proteasome prote-olytic activities occur even in patients with insignificant or no weight loss strongly supports the concept that the pathogenic mechanisms ultimately leading to the phenotypic pattern of CC operate early during the clinical course of human neoplastic disease.

In 36 patients undergoing thoracothomy for lung cancer, Jagoe et al. [24] demonstrated an increase of skeletal muscle mRNA for cathepsin B with respect to healthy controls. mRNA levels for components of the ubiquitin/proteasome pathway were also higher in lung cancer patients than in controls, although the differences did not reach statistical significance. However, it should be noted that in Jagoe's study the majority of patients were in an early disease stage, while only nine out of 36 patients had advanced cancer.

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