Creatine Promotes Cancer Metastasis Through Activation of Smad2/3 (Medicine)

As one of the most popular nutrient supplements, creatine has been used to enhance muscle mass and the function of heathy human subjects. Dietary creatine supplementation has even been used in clinical trial to reverse cachexia of colorectal cancer (CRC) patients, although creatine uptake has been demonstrated to fail to improve either muscle function or life quality of the patients.Studies using subcutaneous injection mouse models showed that creatine uptake suppresses tumor growth, setting creatine as an anti-tumor supplement. However, subcutaneous injection mouse models are not clinically relevant for investigation of tumor progression, and tumor growth is not always coupled with metastasis. Thus, it remains to be elucidated how creatine affects tumor progression, such as metastasis and patient survival.

In a study published in Cell Metabolism, a research group led by Prof. BU Pengcheng at the Institute of Biophysics of the Chinese Academy of Sciences (CAS), collaborating with PIAO Hailong from Dalian Institute of Chemical Physics of the CAS and CHEN Gang from Chinese PLA General Hospital, reported that creatine promotes cancer metastasis through activation of Smad2/3.

To explore creatine function in cancer metastasis, the researchers used an orthotopic mouse model and found that dietary uptake creatine promoted the metastasis of colorectal cancer and breast cancer and shortened mice survival.

They found that the rate-limiting enzyme for creatine synthesis, glycine acyltransferase (GATM), is up-regulated in liver metastasis. Clinically, high levels of GATM were significantly associated with poorer prognosis. GATM promoted CRC liver metastasis and shortened mouse survival, while targeting GATM or creatine transporter SLC6A8 reduced CRC liver metastasis and prolonged mouse survival.

To investigate the mechanism, the researchers performed multi-pathway profiling array and found that creatine upregulated Smad2/3 phosphorylation. Creatine activated Smad2/3 signaling via monopolar spindle 1 (MPS1), a protein kinase associated with mitotic progression and spindle checkpoint.

They further found that creatine also upregulated downstream transcription factor Snail/Slug expression. MPS1 knockdown and specific inhibitor inhibited primary tumor invasion and cancer metastasis by down-regulating Snail/Slug expression, and prolonged mice survival.

This study called for using caution when considering dietary creatine to improve muscle mass or clinical treatment especially for cancer patients. It reported creatine activated Smad2/3 through MPS1, rather than transforming growth factor beta receptor (TGFBR) in the canonical TGF-beta pathway. They also suggested that targeting GATM or MPS1 prevents cancer metastasis, especially metastasis of TGFBR mutant colorectal cancers.

CRC is the third most deadly and fourth most commonly diagnosed cancer in the world, and the incidence has been steadily rising. About 25% of diagnoses cases has metastasized and 70% of CRC patients eventually develop liver metastasis. Hereditary CRC account for 7-10% of all cases, and diet are significant CRC risk factors.

Reference: 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, Creatine promotes cancer metastasis through activation of Smad2/3, Cell Metabolism, 2021, , ISSN 1550-4131, (

Provided by Chinese Academy of Sciences

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