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.
Highlights
Colorectal cancer (CRC) is the third most common type of cancer worldwide with approximately 600,000 annual deaths and 1.2 million new cases every year [1]
The steps that follow for the cell to move forward, include forming adhesion structures to stabilize the protrusion at the leading edge, developing contraction to pull the cell body forward, and releasing adhesion structures at the cell rear to retract the cell towards the direction of motility [8]
We investigate the effect of arginine deprivation on cell migration and invasion in colon cancer and we examine the potential actin regulators involved in this inhibition
Summary
Colorectal cancer (CRC) is the third most common type of cancer worldwide with approximately 600,000 annual deaths and 1.2 million new cases every year [1]. The steps that follow for the cell to move forward, include forming adhesion structures to stabilize the protrusion at the leading edge, developing contraction to pull the cell body forward, and releasing adhesion structures at the cell rear to retract the cell towards the direction of motility [8]. These processes are regulated by the Rho family of small guanosine triphosphatases (GTPases), which includes key enzymes that play a major role in the reorganization of the actin cytoskeleton [9,10]. We investigate the effect of arginine deprivation on cell migration and invasion in colon cancer and we examine the potential actin regulators involved in this inhibition
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