Tilignac Thomas, Temparis Sandrine, Combaret Lydie, Taillandier Daniel, Pouch Marie-Noëlle, Cervek Matjaz, Cardenas Diana M, Le Bricon Thierry, Debiton Eric, Samuels Susan E, Madelmont Jean-Claude, Attaix Didier
Human Nutrition Research Center, Nutrition and Protein Metabolism Unit, Institut National de la Recherche Agronomique de Theix, 63122 Ceyrat, France.
Cancer Res. 2002 May 15;62(10):2771-7.
Chemotherapy has cachectic effects, but it is unknown whether cytostatic agents alter skeletal muscle proteolysis. We hypothesized that chemotherapy-induced alterations in protein synthesis should result in the increased incidence of abnormal proteins, which in turn should stimulate ubiquitin-proteasome-dependent proteolysis. The effects of the nitrosourea cystemustine were investigated in skeletal muscles from both healthy and colon 26 adenocarcinoma-bearing mice, an appropriate model for testing the impact of cytostatic agents. Muscle wasting was seen in both groups of mice 4 days after a single cystemustine injection, and the drug further increased the loss of muscle proteins already apparent in tumor-bearing animals. Cystemustine cured the tumor-bearing mice with 100% efficacy. Surprisingly, within 11 days of treatment, rates of muscle proteolysis progressively decreased below basal levels observed in healthy control mice and contributed to the cessation of muscle wasting. Proteasome-dependent proteolysis was inhibited by mechanisms that include reduced mRNA levels for 20S and 26S proteasome subunits, decreased protein levels of 20S proteasome subunits and the S14 non-ATPase subunit of the 26S proteasome, and impaired chymotrypsin- and trypsin-like activities of the enzyme. A combination of cisplatin and ifosfamide, two drugs that are widely used in the treatment of cancer patients, also depressed the expression of proteasomal subunits in muscles from rats bearing the MatB adenocarcinoma below basal levels. Thus, a down-regulation of ubiquitin-proteasome-dependent proteolysis is observed with various cytostatic agents and contributes to reverse the chemotherapy-induced muscle wasting.
化疗具有恶病质效应，但细胞毒性药物是否会改变骨骼肌蛋白水解尚不清楚。我们推测，化疗引起的蛋白质合成改变应会导致异常蛋白质的发生率增加，进而应会刺激泛素-蛋白酶体依赖性蛋白水解。我们研究了亚硝基脲类药物西司他丁对健康小鼠和荷结肠26腺癌小鼠骨骼肌的影响，这是一种用于测试细胞毒性药物影响的合适模型。单次注射西司他丁4天后，两组小鼠均出现肌肉萎缩，且该药物进一步加剧了荷瘤动物中已明显的肌肉蛋白损失。西司他丁以100%的疗效治愈了荷瘤小鼠。令人惊讶的是，在治疗的11天内，肌肉蛋白水解速率逐渐降至健康对照小鼠中观察到的基础水平以下，并导致肌肉萎缩停止。蛋白酶体依赖性蛋白水解受到多种机制的抑制，包括20S和26S蛋白酶体亚基的mRNA水平降低、20S蛋白酶体亚基和26S蛋白酶体的S14非ATP酶亚基的蛋白水平降低，以及该酶的糜蛋白酶样和胰蛋白酶样活性受损。广泛用于治疗癌症患者的两种药物顺铂和异环磷酰胺的联合使用，也使荷MatB腺癌大鼠肌肉中蛋白酶体亚基的表达低于基础水平。因此，观察到各种细胞毒性药物会下调泛素-蛋白酶体依赖性蛋白水解，并有助于逆转化疗引起的肌肉萎缩。
