Cancer cachexia is characterized by selective depletion of skeletal muscle
protein reserves. Soleus muscles from mice bearing a
cachexia-inducing
tumor (MAC16) showed an increased protein degradation in vitro, as measured by
tyrosine release, when compared with muscles from nontumor-bearing animals. After incubation under conditions that modify different proteolytic systems, lysosomal,
calcium-dependent, and
ATP-dependent proteolysis were found to contribute to the elevated
protein catabolism. Treatment of mice bearing the MAC16
tumor with the
polyunsaturated fatty acid,
eicosapentaenoic acid (EPA), attenuated loss of
body weight and significantly suppressed
protein catabolism in soleus muscles through an inhibition of an
ATP-dependent proteolytic pathway. The
ATP-
ubiquitin-dependent proteolytic pathway is considered to play a major role in muscle catabolism in
cachexia, and functional
proteasome activity, as determined by "
chymotrypsin-like" enzyme activity, was significantly elevated in gastrocnemius muscle of mice bearing the MAC16
tumor as
weight loss progressed. When animals bearing the MAC16
tumor were treated with EPA, functional
proteasome activity was completely suppressed, together with attenuation of the expression of
20S proteasome alpha-subunits and the p42 regulator, whereas there was no effect on the expression of the
ubiquitin-conjugating enzyme (E2(14k)). These results suggest that EPA induces an attenuation of the up-regulation of
proteasome expression in cachectic mice, and this was correlated with an increase in
myosin expression, confirming retention of
contractile proteins. EPA also inhibited growth of the MAC16
tumor in a dose-dependent manner, and this correlated with suppression of the expression of the
20S proteasome alpha-subunits in
tumor cells, suggesting that this may be the mechanism of
tumor growth inhibition. Thus EPA antagonizes loss of skeletal muscle
proteins in
cancer cachexia by down-regulation of
proteasome expression, and this may also be the mechanism for inhibition of
tumor growth.