FOXO1-mediated argininosuccinate lyase transcription inhibits ammonia metabolism and breast cancer cell metastasis

Cancer cells exhibit altered and elevated metabolic processes to meet their increased bioenergetic and biosynthetic demands, leading to the production of ammonia as a byproduct. However, the mechanisms by which tumor cells manage excess ammonia remain poorly understood, despite its critical role in nitrogen metabolism. The urea cycle (UC), a central pathway for ammonia detoxification, has been insufficiently explored in the context of cancer metabolism. In this study, we identify Forkhead box O1 (FOXO1), a transcription factor essential for tumorigenesis and progression, as a key regulator of the UC in breast cancer cells. Specifically, FOXO1 inhibits argininosuccinate lyase (ASL) expression, a crucial enzyme in the UC, leading to reduced ammonia detoxification. Mechanistic analyses reveal that ASL is a direct transcriptional target of FOXO1. Functionally, we demonstrate that FOXO1 modulates the migratory ability of breast cancer cells through the regulation of ASL and arginine metabolism. These findings unveil an unexpected role of FOXO1 in regulating the UC in tumors and highlight a novel mechanism by which breast cancer cells exploit metabolic pathways to support their progression and metastasis. Our study provides valuable insights into cancer metabolism and identifies potential targets for therapeutic intervention.