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.