Human Recombinant Arginase I [HuArgI (Co)-PEG5000]-Induced Arginine Depletion Inhibits Colorectal Cancer Cell Migration and Invasion

Abstract

Purpose: Colorectal cancer (CRC) is the third most common type of cancer worldwide, and it represents over half of all gastrointestinal cancer deaths. Knowing that cancer cells have a high proliferation rate, they require high amounts of amino acids, including arginine. In addition, several tumor types have been shown to downregulate ASS-1 expression, becoming auxotrophic for arginine. Therefore, Arginine deprivation is one of the promising therapeutic approaches to target cancer cells. This can be achieved through the use of a recombinant human arginase, HuArgI(Co)-PEG5000, an arginine degrading enzyme. Methods: In this present study, the cytotoxic effect of HuArgI(Co)-PEG5000 on CRC cell lines (HT-29, Caco-2, Sw837) is examined though cytotoxicity assays. Wound healing assays, invasion assays, and adhesion assays were also performed to detect the effect on metastasis. Results: Wound healing and invasion assays revealed a decrease in cell migration and invasion after treatment with arginase. Cells that were treated with arginase also showed a decrease in adhesion, which coincided with a decrease in RhoA activation, demonstrated though the use of a FRET biosensor to detect RhoA activation in a single cell assay, and a decrease in MMP-9 expression. Treating cells with both arginase and L-citrulline, which significantly restores intracellular arginine levels, reversed the effect of HuArgI(Co)-PEG5000 on cell viability, migration, and invasion. Conclusion: We can, therefore, conclude that colorectal cancer is partially auxotrophic to arginine and that arginine depletion is a potential selective inhibitory approach for motility and invasion in colon cancer cells.

Integrated proteomics and metabolomics reveals the comprehensive characterization of antitumor mechanism underlying Shikonin on colon cancer patient-derived xenograft model

“…Arginine is essential for protein synthesis in adult mammals and plays multiple functions in cell activities. Based on the metabolic vulnerability in tumors, arginine deprivation therapies were developed recently through giving availability to arginine degrading enzymes 18 . In the present study, arginine in mice serum was down-regulated suggesting that the impairment in arginine synthesis and a deficit of exogenous arginine were possibly induced by Shikonin and further inhibit the viability of tumor cells.…”

Combinatory Treatment of Canavanine and Arginine Deprivation Efficiently Targets Human Glioblastoma Cells via Pleiotropic Mechanisms

“…It is known that tumor invasiveness and aggressiveness are highly dependent on malignant cell motility. A negative impact of arginine deprivation as a monotreatment on the motility of glioblastoma, melanoma and colon carcinoma cells was observed [ 25 , 45 , 70 ]. This phenomenon in glioblastoma cells was most probably evoked by the decrease in the content of the positively charged arginylated form of β-actin and polymerized F-actin [ 25 ].…”

Recombinant anthrax lethal toxin inhibits cell motility and invasion in breast cancer cells through the dysregulation of Rho GTPases

“…After treatment with the toxin, cells exhibited an increase in adhesion as shown in the adhesion assay. We have previously shown that overexpression of RhoA leads to an increase in cell adhesion in breast cancer cells, among other tumor types (28,29,(38)(39)(40)(41). RhoA regulates focal adhesion dynamics via its downstream effector Rho-associated protein kinase 1 and the formation of stress fibers needed for migration (28,(38)(39)(40)(41).…”