IMB0901 inhibits muscle atrophy induced by cancer cachexia through MSTN signaling pathway
IMB0901 inhibits muscle atrophy induced by cancer cachexia through MSTN signaling pathway
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IMB0901通过MSTN信号通路抑制癌症恶病质诱导的肌肉萎缩
DOI：
10.1186/s13395-019-0193-2
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发表时间：
2019-03-28
期刊：
影响因子：
4.9
通讯作者：
Chen, Shu-zhen
中科院分区：
文献类型：
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作者：
Liu, Dong;Qiao, Xinran;Chen, Shu-zhen
癌症恶病质作为一种代谢综合征可导致至少25%的癌症死亡。抑制肌肉萎缩是治疗癌症恶病质的主要策略。在这一过程中，肌生长抑制素（myostatin， MSTN）对蛋白质代谢具有抑制蛋白质生物合成和促进蛋白质降解的双重作用。在本研究中，我们将测试MSTN抑制剂IMB0901对癌症恶病质引起的肌肉萎缩的影响。方法建立两种高通量MSTN筛选模型。通过筛选，从化合物文库中筛选出2-（（1-（3,4-二氯苯基）- 1h -吡唑[3,4-d]嘧啶-4-基）氨基）丁烷-1-醇IMB0901。采用体外细胞模型和癌症恶病质致肌肉萎缩C26动物模型测定IMB0901的药理活性。体外和体内研究IMB0901是否能抑制阿霉素对肌肉萎缩的加重作用。结果simb0901抑制MSTN启动子活性，抑制MSTN信号通路，抑制MSTN正反馈调控。在萎缩的C2C12肌管中，IMB0901具有降低MSTN表达和调节c26条件培养基（CM）激活的MSTN信号通路的有效作用。在C2C12肌管中，CM下调了肌球蛋白重链（MyHC）、肌源性分化1 （MyoD）和肌原素（MyoG）这三种常见肌管标志物的表达，而IMB0901可以通过减少ubiquitin介导的蛋白水解和增强AKT/ mtor介导的蛋白合成来有效逆转这一变化。在C26动物模型中，IMB0901减轻了体、股四头肌和肝脏的失重，并保护了股四头肌细胞形态。此外，IMB0901在体内降低了股四头肌中两种E3连接酶Atrogin-1和MuRF-1的表达。在细胞水平上，IMB0901对顺铂、阿霉素、吉西他滨三种化疗药物的抗肿瘤作用无影响，降低了阿霉素诱导的C2C12肌管中MSTN的上调。IMB0901不影响阿霉素对C26肿瘤的抑制作用，延缓了C26肿瘤和阿霉素引起的肌肉和脂肪组织的减重。结论simb0901通过抑制泛素介导的蛋白质水解和促进蛋白质合成，抑制癌症恶病质诱导的肌肉萎缩。这些研究结果共同表明，IMB0901是治疗癌症恶病质引起的肌肉萎缩的有希望的先导化合物。
BackgroundCancer cachexia as a metabolic syndrome can lead to at least 25% of cancer deaths. The inhibition of muscle atrophy is a main strategy to treat cancer cachexia. In this process, myostatin (MSTN) can exert a dual effect on protein metabolism, including inhibition of protein biosynthesis and enhancement of protein degradation. In this study, we will test the effect on muscle atrophy induced by cancer cachexia of IMB0901, a MSTN inhibitor.MethodsTwo high-throughput screening models against MSTN were developed. By screening, IMB0901, 2-((1-(3,4-dichlorophenyl)-1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) butan-1-ol, was picked out from the compound library. The in vitro cell model and the C26 animal model of muscle atrophy induced by cancer cachexia were used to determine the pharmacological activity of IMB0901. Whether IMB0901 could inhibit the aggravating effect of doxorubicin on muscle wasting was examined in vitro and in vivo.ResultsIMB0901 inhibited the MSTN promoter activity, the MSTN signaling pathway, and the MSTN positive feedback regulation. In atrophied C2C12 myotubes, IMB0901 had a potent efficiency of decreasing MSTN expression and modulating MSTN signaling pathway which was activated by C26-conditioned medium (CM). In C2C12 myotubes, the expressions of three common myotube markers, myosin heavy chain (MyHC), myogenic differentiation 1 (MyoD), and myogenin (MyoG), were downregulated by CM, which could be efficiently reversed by IMB0901 via reduction of ubiquitin-mediated proteolysis and enhancement of AKT/mTOR-mediated protein synthesis. In the C26 animal model, IMB0901 mitigated the weight loss of body, quadricep and liver, and protected the quadriceps cell morphology. Furthermore, IMB0901 decreased the expression of two E3 ligases Atrogin-1 and MuRF-1 in the quadriceps in vivo. At the cellular level, IMB0901 had no influence on anti-tumor effect of three chemotherapeutic agents (cisplatin, doxorubicin, and gemcitabine) and lowered doxorubicin-induced upregulation of MSTN in C2C12 myotubes. IMB0901 did not affect the inhibitory effect of doxorubicin on C26 tumor and delayed the weight loss of muscle and adipose tissue caused by C26 tumor and doxorubicin.ConclusionsIMB0901 inhibits muscle atrophy induced by cancer cachexia by suppressing ubiquitin-mediated proteolysis and promoting protein synthesis. These findings collectively suggest that IMB0901 is a promising leading compound for the management of muscle atrophy induced by cancer cachexia.