Arginase-1 inhibition reduces migration ability and metastatic colonization of colon cancer cells

Abstract

Background Arginase-1 (ARG1), a urea cycle-related enzyme, catalyzes the hydrolysis of arginine to urea and ornithine, which regulates the proliferation, differentiation, and function of various cells. However, it is unclear whether ARG1 controls the progression and malignant alterations of colon cancer. Methods We established metastatic colonization mouse model and ARG1 overexpressing murine colon cancer CT26 cells to investigate whether activation of ARG1 was related to malignancy of colon cancer cells in vivo. Living cell numbers and migration ability of CT26 cells were evaluated in the presence of ARG inhibitor in vitro. Results Inhibition of arginase activity significantly suppressed the proliferation and migration ability of CT26 murine colon cancer cells in vitro. Overexpression of ARG1 in CT26 cells reduced intracellular l-arginine levels, enhanced cell migration, and promoted epithelial-mesenchymal transition. Metastatic colonization of CT26 cells in lung and liver tissues was significantly augmented by ARG1 overexpression in vivo. ARG1 gene expression was higher in the tumor tissues of liver metastasis than those of primary tumor, and arginase inhibition suppressed the migration ability of HCT116 human colon cancer cells. Conclusion Activation of ARG1 is related to the migration ability and metastatic colonization of colon cancer cells, and blockade of this process may be a novel strategy for controlling cancer malignancy.

Recent advances in DDAH1 inhibitor design and discovery: insights from structure–activity relationships and X-ray crystal structures

“…This is expected to increase endogenous L-arginine concentrations, enabling NO production (via NOS) in non-targeted cells thus reducing cell toxicity. Therefore, dual DDAH1/arginase inhibition is proposed as be a useful strategy for selectively targeting tumor growth in multiple cancer phenotypes 11,[43][44][45] whilst maintaining NO homeostasis in healthy cells. More work assessing in vivo effects/benets of dual DDAH1/arginase and DDAH1/NOS inhibition is needed as knowledge in this area is currently lacking.…”

Hydrogel‐Based Strategies to Enhance T‐Cell Performance for Solid Tumor Immunotherapy

“…[ 143 ] In addition, overexpression of arginase‐1 in colorectal cancer revealed an increased migratory phenotype attributed to heightened metastasis. [ 144 ] These results suggest that inhibiting arginase with hydrogel approaches may be a powerful method of anti‐tumor effects in many different types of cancers.…”

Genetics of enzymatic dysfunctions in metabolic disorders and cancer

“…The fifth reaction in the urea cycle is catalyzed by ARG1, involved in the hydrolysis of arginine to ornithine and urea, which regulate the proliferation, differentiation, and function of different cell types. Arginase-1 deficiency is identified by either a complete or partial absence of the arginase enzyme in the liver and red blood cells, with symptoms that can include vomiting, poor growth, seizures, and stiff muscles with increased reflexes (spasticity) ( 40 , 41 ). Increased expression of arginases (either Arg1 or Arg2) is considered a poor prognostic factor in several types of cancer, including lung cancer ( 42 , 43 ), head and neck cancer ( 44 ), neuroblastoma ( 45 ), acute myeloid leukemia ( 46 ), pancreatic ductal carcinoma ( 47 ), ovarian carcinoma ( 48 ), and colorectal cancer ( 49 ).…”