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Open AccessArticle

Metformin Inhibits the Urea Cycle and Reduces Putrescine Generation in Colorectal Cancer Cell Lines

1
Department of Anatomy, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
2
Lab of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University, Chongqing 400016, China
3
Chongqing Three Gorges Medical College, Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing 404120, China
*
Author to whom correspondence should be addressed.
Academic Editor: Sergei Boichuk
Molecules 2021, 26(7), 1990; https://doi.org/10.3390/molecules26071990
Received: 22 February 2021 / Revised: 24 March 2021 / Accepted: 28 March 2021 / Published: 1 April 2021
(This article belongs to the Special Issue Targeting of Signaling Pathways for Cancer Therapy)
The urea cycle (UC) removes the excess nitrogen and ammonia generated by nitrogen-containing compound composites or protein breakdown in the human body. Research has shown that changes in UC enzymes are not only related to tumorigenesis and tumor development but also associated with poor survival in hepatocellular, breast, and colorectal cancers (CRC), etc. Cytoplasmic ornithine, the intermediate product of the urea cycle, is a specific substrate for ornithine decarboxylase (ODC, also known as ODC1) for the production of putrescine and is required for tumor growth. Polyamines (spermidine, spermine, and their precursor putrescine) play central roles in more than half of the steps of colorectal tumorigenesis. Given the close connection between polyamines and cancer, the regulation of polyamine metabolic pathways has attracted attention regarding the mechanisms of action of chemical drugs used to prevent CRC, as the drug most widely used for treating type 2 diabetes (T2D), metformin (Met) exhibits antitumor activity against a variety of cancer cells, with a vaguely defined mechanism. In addition, the influence of metformin on the UC and putrescine generation in colorectal cancer has remained unclear. In our study, we investigated the effect of metformin on the UC and putrescine generation of CRC in vivo and in vitro and elucidated the underlying mechanisms. In nude mice bearing HCT116 tumor xenografts, the administration of metformin inhibited tumor growth without affecting body weight. In addition, metformin treatment increased the expression of monophosphate (AMP)-activated protein kinase (AMPK) and p53 in both HCT116 xenografts and colorectal cancer cell lines and decreased the expression of the urea cycle enzymes, including carbamoyl phosphate synthase 1 (CPS1), arginase 1 (ARG1), ornithine trans-carbamylase (OTC), and ODC. The putrescine levels in both HCT116 xenografts and HCT116 cells decreased after metformin treatment. These results demonstrate that metformin inhibited CRC cell proliferation via activating AMPK/p53 and that there was an association between metformin, urea cycle inhibition and a reduction in putrescine generation. View Full-Text
Keywords: metformin; colorectal cancer (CRC); p53; proliferation; urea cycle; human colorectal cancer HCT116 cell line; CPS1; ARG1; OTC; ODC; putrescine metformin; colorectal cancer (CRC); p53; proliferation; urea cycle; human colorectal cancer HCT116 cell line; CPS1; ARG1; OTC; ODC; putrescine
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MDPI and ACS Style

Zhang, T.; Hu, L.; Tang, J.-F.; Xu, H.; Tian, K.; Wu, M.-N.; Huang, S.-Y.; Du, Y.-M.; Zhou, P.; Lu, R.-J.; He, S.; Xu, J.-M.; Si, J.-J.; Li, J.; Chen, D.-L.; Ran, J.-H. Metformin Inhibits the Urea Cycle and Reduces Putrescine Generation in Colorectal Cancer Cell Lines. Molecules 2021, 26, 1990. https://doi.org/10.3390/molecules26071990

AMA Style

Zhang T, Hu L, Tang J-F, Xu H, Tian K, Wu M-N, Huang S-Y, Du Y-M, Zhou P, Lu R-J, He S, Xu J-M, Si J-J, Li J, Chen D-L, Ran J-H. Metformin Inhibits the Urea Cycle and Reduces Putrescine Generation in Colorectal Cancer Cell Lines. Molecules. 2021; 26(7):1990. https://doi.org/10.3390/molecules26071990

Chicago/Turabian Style

Zhang, Tao; Hu, Ling; Tang, Jia-Feng; Xu, Hang; Tian, Kuan; Wu, Meng-Na; Huang, Shi-Ying; Du, Yu-Mei; Zhou, Peng; Lu, Rui-Jin; He, Shuang; Xu, Jia-Mei; Si, Jian-Jun; Li, Jing; Chen, Di-Long; Ran, Jian-Hua. 2021. "Metformin Inhibits the Urea Cycle and Reduces Putrescine Generation in Colorectal Cancer Cell Lines" Molecules 26, no. 7: 1990. https://doi.org/10.3390/molecules26071990

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