The
ubiquitin-
proteasome proteolytic pathway plays a major role in degradation of myofibrillar
proteins in skeletal muscle during
cancer cachexia. The end-product of this pathway is
oligopeptides and these are degraded by the extralysomal
peptidase tripeptidyl-peptidase II (TPPII) together with various
aminopeptidases to form tripeptides and
amino acids. To investigate if a relationship exists between the activity of the
proteasome and TPPII, functional activities have been measured in gastrocnemius muscle of mice bearing the MAC16 tumour, and with varying extents of
weight loss. TPPII activity was quantitated using the specific substrate Ala-Ala-Phe-7-amido-4-methylcoumarin, while
proteasome activity was determined as the '
chymotrypsin-like' enzyme activity. Both
proteasome proteolytic activity and TPPII activity increased in parallel with increasing
weight loss, reaching a maximum at 16%
weight loss, after which there was a progressive decrease in activity for both
proteases with increasing
weight loss. In murine myotubes, proteolysis-inducing factor, which is a sulphated
glycoprotein produced by
cachexia-inducing tumours, induced an increase in activity of both
proteasome and TPPII, with an identical dose-response curve, and both activities were inhibited by
eicosapentaenoic acid. These results suggest that the activities of both the
proteasome and TPPII are regulated in a parallel manner in
cancer cachexia, and that both are induced by the same factor and probably have the same intracellular signalling pathways and
transcription factors.