Cancer cachexia is regulated by selective targeting of skeletal muscle gene products
Cancer cachexia is regulated by selective targeting of skeletal muscle gene products
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DOI：
10.1172/jci200420174
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发表时间：
2004-08-01
影响因子：
15.9
通讯作者：
Guttridge, DC
中科院分区：
文献类型：
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作者：
Acharyya, S;Ladner, KJ;Guttridge, DC
恶病质是一种以骨骼肌消耗为特征的综合征，占所有癌症死亡的近三分之一。细胞因子和肿瘤因子通过抑制肌肉基因产物介导消耗，但这些恶病质因子靶向的确切产物尚不清楚。由于它们与肌肉结构的功能相关性，这些靶点被假定为代表肌原纤维蛋白，但这些蛋白质是否以一般或选择性方式受到调节也不清楚。在这里，我们证明，在体外和体内模型的肌肉萎缩，恶病质因子是非常有选择性的靶向肌球蛋白重链。在肌管和小鼠肌肉中，TNF-α加IFN-γ通过RNA依赖性机制强烈降低肌球蛋白表达。同样，小鼠的结肠26肿瘤导致这种肌原纤维蛋白的选择性减少，这种减少与消耗有关。然而，在这些条件下，肌球蛋白的损失与泛素依赖的蛋白酶体途径，这表明用于调节肌肉蛋白的表达的机制可能是恶病质因子特异性。这些结果揭示了消瘦不是由于肌肉蛋白的普遍下调，而是高度选择性地针对消瘦状态期间靶向的蛋白质，从而为癌症恶病质提供了新的斗争。
Cachexia is a syndrome characterized by wasting of skeletal muscle and contributes to nearly one-third of all cancer deaths. Cytokines and tumor factors mediate wasting by suppressing muscle gene products, but exactly which products are targeted by these cachectic factors is not well understood. Because of their functional relevance to muscle architecture, such targets are presumed to represent myofibrillar proteins, but whether these proteins are regulated in a general or a selective manner is also unclear. Here we demonstrate, using in vitro and in vivo models of muscle wasting, that cachectic factors are remarkably selective in targeting myosin heavy chain. In myotubes and mouse muscles, TNF-alpha plus IFN-gamma strongly reduced myosin expression through an RNA-dependent mechanism. Likewise, colon-26 tumors in mice caused the selective reduction of this myofibrillar protein, and this reduction correlated with wasting. Under these conditions, however, loss of myosin was associated with the ubiquitin-dependent proteasome pathway, which suggests that mechanisms used to regulate the expression of muscle proteins may be cachectic factor specific. These results shed new fight on cancer cachexia by revealing that wasting does not result from a general downregulation of muscle proteins but rather is highly selective as to which proteins are targeted during the wasting state.