Elevated arginine levels in liver tumors promote metabolic reprogramming and tumor growth

Arginine auxotropy, due to reduced expression of urea cycle genes, is common in cancer. However, little is known about the levels of arginine in these cancers. Here, we report that arginine levels are elevated in hepatocellular carcinoma (HCC) despite reduced expression of urea cycle enzymes. Liver tumors accumulate high levels specifically of arginine via increased uptake and, more importantly, via suppression of arginine-to-polyamine conversion due to reduced arginase 1 (ARG1) and agmatinase (AGMAT) expression. Furthermore, the high levels of arginine are required for tumor growth. Mechanistically, high levels of arginine promote tumorigenesis via transcriptional regulation of metabolic genes, including upregulation of asparagine synthetase (ASNS). ASNS-derived asparagine further enhances arginine uptake, creating a positive feedback loop to sustain high arginine levels and oncogenic metabolism. Thus, arginine is a novel second messenger-like molecule that reprograms metabolism to promote tumor growth.