Myostatin is a novel tumoral factor that induces cancer cachexia (Retracted article. See vol. 473, pg. 1111, 2016)
Myostatin is a novel tumoral factor that induces cancer cachexia (Retracted article. See vol. 473, pg. 1111, 2016)
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DOI：
10.1042/bj20112024
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发表时间：
2012-08-15
影响因子：
4.1
通讯作者：
Sharma, Mridula
中科院分区：
文献类型：
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作者：
Lokireddy, Sudarsanareddy;Wijesoma, Isuru Wijerupage;Sharma, Mridula
体液和肿瘤因素通过增加蛋白质降解共同促进癌症诱导的骨骼肌萎缩。虽然几种体液蛋白，即TNF α（肿瘤坏死因子α）和IL（白细胞介素）-6，已被证明可诱导骨骼肌萎缩，但缺乏有关癌症恶病质期间导致肌肉萎缩的肿瘤因素的信息。因此，在本研究中，我们已经确定了C26结肠癌细胞的分泌组，以确定参与癌症诱导的骨骼肌萎缩的肿瘤因子。在本研究中，我们发现肌生长抑制素，一个前趋化的TGF β（转化生长因子β）超家族成员，是丰富的C26细胞分泌。与恶病质期间的肌生长抑制素信号传导一致，用C26 CM（条件培养基）处理分化的C2 C12肌管导致肌管萎缩，这是由于肌肉特异性E3连接酶、atrogin-1和MuRF 1（肌肉环指蛋白1）的上调以及泛素蛋白酶体途径的活性增强。此外，C26 CM还激活ActRIIB（激活素受体II型B）/Smad和NF-κ B（核因子κ B）信号传导，并降低IGF-I（胰岛素样生长因子1）/P13 K（磷酸肌醇3-激酶）/Akt途径的活性，这是骨骼肌中肌生长抑制素作用的三个显著分子特征。肌生长抑制素的拮抗剂防止了C26 CM诱导的肌细胞培养物的消耗，进一步证实了肿瘤肌生长抑制素可能是癌症恶病质发病机制的关键因素。最后，我们表明，C26 CM治疗诱导自噬-溶酶体途径，减少肌管中线粒体的数量。这两个以前未报告的观察结果在从C26荷瘤小鼠收集的骨骼肌中重现。
Humoral and tumoral factors collectively promote cancer-induced skeletal muscle wasting by increasing protein degradation. Although several humoral proteins, namely TNF alpha (tumour necrosis factor alpha) and IL (interleukin)-6, have been shown to induce skeletal muscle wasting, there is a lack of information regarding the tumoral factors that contribute to the atrophy of muscle during cancer cachexia. Therefore, in the present study, we have characterized the secretome of C26 colon cancer cells to identify the tumoral factors involved in cancer-induced skeletal muscle wasting. In the present study, we show that myostatin, a procachectic TGF beta (transforming growth factor beta) superfamily member, is abundantly secreted by C26 cells. Consistent with myostatin signalling during cachexia, treating differentiated C2C12 myotubes with C26 CM (conditioned medium) resulted in myotubular atrophy due to the up-regulation of muscle-specific E3 ligases, atrogin-1 and MuRF1 (muscle RING-finger protein 1), and enhanced activity of the ubiquitin proteasome pathway. Furthermore, the C26 CM also activated ActRIIB (activin receptor type II B)/Smad and NF-kappa B (nuclear factor kappa B) signalling, and reduced the activity of the IGF-I (insulin-like growth factor 1)/P13K (phosphoinositide 3-kinase)/Akt pathway, three salient molecular features of myostatin action in skeletal muscles. Antagonists to myostatin prevented C26 CM-induced wasting in muscle cell cultures, further confirming that tumoral myostatin may be a key contributor in the pathogenesis of cancer cachexia. Finally, we show that treatment with C26 CM induced the autophagy-lysosome pathway and reduced the number of mitochondria in myotubes. These two previously unreported observations were recapitulated in skeletal muscles collected from C26 tumour-bearing mice.