GDF-15 in tumor-derived exosomes promotes muscle atrophy via Bcl-2/caspase-3 pathway.
GDF-15 in tumor-derived exosomes promotes muscle atrophy via Bcl-2/caspase-3 pathway.
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肿瘤源性外泌体中的 GDF-15 通过 Bcl-2/caspase-3 途径促进肌肉萎缩
DOI：
10.1038/s41420-022-00972-z
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发表时间：
2022-04-04
影响因子：
7
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Zhang W;Sun W;Gu X;Miao C;Feng L;Shen Q;Liu X;Zhang X
肿瘤源性外泌体是癌症恶病质的新兴介质，癌症恶病质是一种以骨骼肌质量和功能严重丧失为特征的多因素综合征。我们之前的研究表明C26结肠肿瘤细胞外泌体中的microRNAs参与了肌肉萎缩的诱导。在这里，我们重点研究肿瘤源性外泌体中的蛋白质，这可能也有助于癌症恶病质的发展。比较恶病质C26外泌体和非恶病质MC38外泌体的蛋白谱结果表明，C26外泌体富含生长分化因子15 （GDF-15）。Western blotting分析证实，与MC38细胞相比，C26细胞和C26外泌体中的GDF-15水平较高。动物实验结果还表明，GDF-15在C26荷瘤小鼠的肿瘤组织、血清外泌体和腓肠肌组织中含量丰富。GDF-15蛋白可通过调控Bcl-2/caspase-3通路直接诱导培养的C2C12肌管肌肉萎缩。此外，在MC38细胞中过表达GDF-15可以增加MC38条件培养基或外泌体诱导肌肉萎缩的效力。C26细胞中GDF-15的敲低降低了C26条件培养基或外泌体诱导肌肉萎缩的效力。这些结果表明，肿瘤源性外泌体中的GDF-15可能有助于肌肉萎缩的诱导，也支持了靶向GDF-15治疗癌症恶病质的可能性。
Tumor-derived exosomes are emerging mediators of cancer cachexia, a kind of multifactorial syndrome characterized by serious loss of skeletal muscle mass and function. Our previous study had showed that microRNAs in exosomes of C26 colon tumor cells were involved in induction of muscle atrophy. Here, we focus on studying proteins in tumor-derived exosomes which might also contribute to the development of cancer cachexia. Results of comparing the protein profiles of cachexic C26 exosomes and non-cachexic MC38 exosomes suggested that growth differentiation factor 15 (GDF-15) was rich in C26 exosomes. Western blotting analysis confirmed the higher levels of GDF-15 in C26 cells and C26 exosomes, compared with that of MC38 cells. Results of animal study also showed that GDF-15 was rich in tumor tissues, serum exosomes, and gastrocnemius (GA) muscle tissues of C26 tumor-bearing mice. GDF-15 protein could directly induce muscle atrophy of cultured C2C12 myotubes via regulating Bcl-2/caspase-3 pathways. What’s more, overexpression of GDF-15 in MC38 cells could increase the potency of MC38 conditioned medium or exosomes in inducing muscle atrophy. Knockdown of GDF-15 in C26 cells decreased the potency of C26 conditioned medium or exosomes in inducing muscle atrophy. These results suggested that GDF-15 in tumor-derived exosomes could contribute to induction of muscle atrophy and also supported the possibility of targeting GDF-15 in treatment of cancer cachexia.
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