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

Abstract

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.

Targeting p53 pathways: mechanisms, structures and advances in therapy

“…Tumor cells produce large amounts of ammonia during amino acid metabolism, and this ammonia can serve as a nitrogen source for tumor growth. 108 , 109 p53 regulates ammonia content in tumor cells through the urea cycle. p53 regulates ammonia content in tumor cells by inhibiting the expression of three key enzyme genes in the urea cycle of tumor cells, CPS1, OTC and ARG1, which ultimately inhibits tumor growth.…”

Metformin Treatment Induces Different Response in Pheochromocytoma/Paraganglioma Tumour Cells and in Primary Fibroblasts

“…Recently, metformin has been proposed as a potential antitumoral drug due to its inhibitory effect on growth and survival of different cell lines, including neuroblastoma [9], glioblastoma cells [10,11], and rat PPGL cells [12]. Its anticarcinogenic activity was also supported by evidence obtained from epidemiological studies and clinical trials on endometrial [13], colorectal [14], prostate [15], breast [16], adrenocortical [17], and head and neck cancers [18]. However, whether metformin plays a role in inhibiting the migration of PPGL cells has yet to be explored.…”

A Non-Conventional Platinum Drug against a Non-Small Cell Lung Cancer Line

“…These compounds have been used successfully by the authors as biocompatible polydentate ligands to form chelates with Pt(II) and Pd(II) cations [ 8 , 9 , 10 , 12 , 13 , 15 , 16 , 17 ]. Although these polyamines are known to be closely related to neoplastic growth and cancer progression [ 25 , 26 , 27 , 28 , 29 ], this effect is not observed upon coordination to a metal center. Instead, they allow the formation of stable complexes with intermediate-to-soft transition ions (through nitrogen binding) that may be transported into the cell through the specific polyamine channels [ 30 , 31 ], which is an advantage for attaining a high bioavailability of the potential drugs at their pharmacological targets (namely DNA).…”