Whitehouse A S, Smith H J, Drake J L, Tisdale M J
Pharmaceutical Sciences Research Institute, Aston University, Birmingham B4 7ET, United Kingdom.
Cancer Res. 2001 May 1;61(9):3604-9.
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.
癌症恶病质的特征是骨骼肌蛋白质储备选择性耗竭。与未患肿瘤动物的肌肉相比，携带可诱导恶病质肿瘤（MAC16）的小鼠的比目鱼肌在体外显示出蛋白质降解增加，这通过酪氨酸释放来衡量。在改变不同蛋白水解系统的条件下孵育后，发现溶酶体、钙依赖性和ATP依赖性蛋白水解均导致蛋白质分解代谢升高。用多不饱和脂肪酸二十碳五烯酸（EPA）治疗携带MAC16肿瘤的小鼠，可减轻体重减轻，并通过抑制ATP依赖性蛋白水解途径显著抑制比目鱼肌中的蛋白质分解代谢。ATP-泛素依赖性蛋白水解途径被认为在恶病质的肌肉分解代谢中起主要作用，随着体重减轻的进展，通过“胰凝乳蛋白酶样”酶活性测定的功能性蛋白酶体活性在携带MAC16肿瘤的小鼠的腓肠肌中显著升高。当用EPA治疗携带MAC16肿瘤的动物时，功能性蛋白酶体活性被完全抑制，同时20S蛋白酶体α亚基和p42调节因子的表达减弱，而对泛素结合酶（E2(14k)）的表达没有影响。这些结果表明，EPA诱导恶病质小鼠蛋白酶体表达上调的减弱，这与肌球蛋白表达的增加相关，证实了收缩蛋白的保留。EPA还以剂量依赖性方式抑制MAC16肿瘤的生长，这与肿瘤细胞中20S蛋白酶体α亚基表达的抑制相关，表明这可能是肿瘤生长抑制的机制。因此，EPA通过下调蛋白酶体表达来拮抗癌症恶病质中骨骼肌蛋白的丢失，这也可能是抑制肿瘤生长的机制。
