Cell Metabolism, 2 April, 2021, DOI：https://doi.org/10.1016/j.cmet.2021.03.009
Creatine promotes cancer metastasis through activation of Smad2/3
Liwen Zhang, Zijing Zhu, Huiwen Yan, Wen Wang, Zhenzhen Wu, Fei Zhang, Qixiang Zhang, Guizhi Shi, Junfeng Du, Huiyun Cai, Xuanxuan Zhang, David Hsu, Pu Gao, Hai-long Piao, Gang Chen, Pengcheng Bu
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.