Critical role of argininosuccinate lyase in TAp73-mediated proliferating tumor cells

Abstract

The dysregulation of the urea cycle resulting in an excessive buildup of ammonia is identified as a pivotal mechanism driving tumor progression. In particular, argininosuccinate lyase (ASL) is crucial for cancer cell proliferation, cleaves argininosuccinic acid to produce arginine and fumarate in the urea cycle. However, the mechanisms controlling ASL expression in cancer cells remain unclear. Herein, we found that TAp73, a transcription factor within the p53 family, regulates the urea cycle pathway in tumor cells with mutant or null p53. Deletion of TAp73 led to increased accumulation of ammonia and changes in urea cycle metabolites. Subsequent experimentation involving the suppression of TAp73 substantiated its pronounced capability in impeding tumor proliferation and tumorigenicity in both in vitro and in vivo settings. Chromatin immunoprecipitation revealed that TAp73 could bind to specific sequences in the ASL promoter, thus promoting ASL expression, increasing intracellular arginine, and reducing ammonia levels. This investigation undertook a clinical scrutiny of TAp73 expression levels in tumor patients' transcriptomes, revealing an inverse relationship between TAp73 expression and patient survival. These results suggested that TAp73 led to abnormalities in the urea cycle by enhancing ASL expression and will be an important factor in promoting tumor proliferation and a potential target for tumor drugs.