MECHANISM OF MUSCLE PROTEIN-DEGRADATION INDUCED BY A CANCER CACHECTICFACTOR

A proteolysis-inducing factor (PIF) isolated from a cachexia-inducing murine tumour (MAC16) produced a decrease in body weight (1.6 g, P les s than or equal to 0.01 compared with control subjects) within 24 h af ter i.v. administration to non-tumour-bearing mice. Weight loss was as sociated with significant decreases in the weight of the spleen and so leus and gastrocnemius muscles, with no effect on the weight of the he art or kidney and with an increase in weight of the liver. Protein deg radation in isolated soleus muscle was significantly increased in mice bearing the MAC16 tumour. To define which proteolytic pathways contri bute to this increase, soleus muscles from mice bearing the MAC16 tumo ur and non-tumour-bearing animals administered PIF were incubated unde r conditions that modify different proteolytic systems, In mice bearin g the MAC16 tumour, there were increases in both cathepsin B and L, an d the Ca2+-dependent lysosomal and ATP-dependent pathways were found t o contribute to the increased proteolysis; whereas, in PIF-injected an imals, there was activation only of the ATP-dependent pathway. Further studies in mice bearing the MAC16 tumour have provided evidence for i ncreased levels of ubiquitin-conjugated proteins and increased mRNA le vels for the 14 kDa ubiquitin carrier protein E2 and the C9 proteasome subunit in gastrocnemius muscle, suggesting activation of the ATP-ubi quitin-dependent proteolytic pathway. A monoclonal antibody to PIF att enuated the enhanced protein degradation in soleus muscle from mice be aring the MAC16 tumour, confirming that PIF is responsible for the los s of skeletal muscle in cachectic mice.