Arginine Deprivation Induces Quiescence and Confers Vulnerability to Ferroptosis in Colorectal Cancer

Metabolic reprogramming is a hallmark of cancer. Rewiring of amino acid metabolic processes provides the basis for amino acid deprivation therapies. In this study, we found that arginine biosynthesis is limited in colorectal cancer because of the deficiency of ornithine transcarbamylase. Accordingly, colorectal cancer cells met the demand for arginine by increasing external uptake. The addiction to environmental arginine resulted in the susceptibility of colorectal cancer to arginine deprivation, which dramatically decreased proliferation in colorectal cancer cells and promoted these cells to enter a reversible quiescence state. Arginine deprivation induced quiescence by activating the AMPK-p53-p21 pathway. RNA sequencing data indicated that colorectal cancer cells may be vulnerable to ferroptosis during arginine deprivation and the combination of ferroptosis inducers and arginine deprivation strongly impeded tumor growth in vivo. These findings suggest that dietary modification combined with ferroptosis induction could be a potential therapeutic strategy for colorectal cancer. Significance: Colorectal cancer dependency on arginine uptake creates a metabolic vulnerability to arginine deficiency that causes cell cycle arrest and ferroptosis sensitivity, highlighting arginine deprivation plus ferroptosis induction as a promising treatment.