Creatine promotes cancer metastasis through activation of Smad2/3
Creatine promotes cancer metastasis through activation of Smad2/3
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肌酸通过激活 Smad2/3 促进癌症转移
DOI：
10.1016/j.cmet.2021.03.009
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发表时间：
2021-06-01
期刊：
影响因子：
29
通讯作者：
Bu, Pengcheng
中科院分区：
文献类型：
--
作者：
Zhang, Liwen;Zhu, Zijing;Bu, Pengcheng
作为最受欢迎的营养补充剂之一，肌酸已被高度用于增加肌肉质量和提高运动表现。在这里，我们使用原位小鼠模型报告了肌酸的副作用，表明肌酸促进结直肠癌和乳腺癌转移并缩短小鼠生存期。我们发现，甘氨酸脒基转移酶（GATM），肌酸合成的限速酶，在肝转移瘤中上调。饮食摄取，或GATM介导的肌酸从头合成，通过单极纺锤体1（MPS1）激活的Smad2和Smad3磷酸化上调Snail和Slug表达，增强癌症转移并缩短小鼠生存期。GATM敲除或MPS1抑制通过下调Snail和Slug抑制癌症转移并有益于小鼠存活。我们的研究结果呼吁在考虑饮食肌酸改善肌肉质量或治疗疾病时要谨慎使用，并表明靶向GATM或MPS1可预防癌症转移，特别是转化生长因子β受体突变型结直肠癌的转移。
As one of the most popular nutrient supplements, creatine has been highly used to increase muscle mass and improve exercise performance. Here, we report an adverse effect of creatine using orthotopic mouse models, showing that creatine promotes colorectal and breast cancer metastasis and shortens mouse survival. We show that glycine amidinotransferase (GATM), the rate-limiting enzyme for creatine synthesis, is upregulated in liver metastases. Dietary uptake, or GATM-mediated de novo synthesis of creatine, enhances cancer metastasis and shortens mouse survival by upregulation of Snail and Slug expression via monopolar spindle 1 (MPS1)-activated Smad2 and Smad3 phosphorylation. GATM knockdown or MPS1 inhibition suppresses cancer metastasis and benefits mouse survival by downregulating Snail and Slug. Our findings call for using caution when considering dietary creatine to improve muscle mass or treat diseases and suggest that targeting GATM or MPS1 prevents cancer metastasis, especially metastasis of transforming growth factor beta receptor mutant colorectal cancers.