2. Academic Validation
  3. Creatine promotes cancer metastasis through activation of Smad2/3

Creatine promotes cancer metastasis through activation of Smad2/3

  • Cell Metab. 2021 Jun 1;33(6):1111-1123.e4. doi: 10.1016/j.cmet.2021.03.009.
Liwen Zhang 1,  Zijing Zhu 1,  Huiwen Yan 2,  Wen Wang 3,  Zhenzhen Wu 2,  Fei Zhang 1,  Qixiang Zhang 4,  Guizhi Shi 5,  Junfeng Du 6,  Huiyun Cai 7,  Xuanxuan Zhang 1,  David Hsu 8,  Pu Gao 4,  Hai-Long Piao 9,  Gang Chen 10,  Pengcheng Bu 11
Affiliations

Affiliations

  • 1 Key Laboratory of RNA Biology, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 Key Laboratory of RNA Biology, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 3 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
  • 4 College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 5 Laboratory Animal Research Center, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 6 Department of General Surgery, the 7(th) Medical Center, Chinese PLA General Hospital, Beijing 100700, China; The 2(nd) School of Clinical Medicine, Southern Medical University, Guangdong 510515, China; Medical Department of General Surgery, the 1st Medical Center, Chinese PLA General Hospital, Beijing 100853, China.
  • 7 Department of General Surgery, the 7(th) Medical Center, Chinese PLA General Hospital, Beijing 100700, China.
  • 8 Department of Medicine, Duke University School of Medicine, Durham 27708, USA.
  • 9 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. Electronic address: [email protected].
  • 10 Department of General Surgery, the 7(th) Medical Center, Chinese PLA General Hospital, Beijing 100700, China. Electronic address: [email protected].
  • 11 Key Laboratory of RNA Biology, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: [email protected].
PMID: 33811821 DOI: 10.1016/j.cmet.2021.03.009
Abstract

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.

Keywords

GATM; MPS1; SLC6A8; Smad2; Smad3; breast cancer; colorectal cancer; creatine; metastasis.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12401
    99.67%, MPS1 Inhibitor