牛磺酸通过靶向ASL作为尿素循环天然抑制因子抑制肝细胞癌生长的机制

Abstract

Hepatocellular carcinoma (HCC) has become the leading cause of global cancer-related mortality, which raises the demand for optimized therapeutic routes. The semi-essential micronutrient taurine has been gradually identified as a pivotal player linked to various diseases. Nevertheless, the metabolic impacts of taurine on hepatocellular carcinoma remain elusive. Here, we report that taurine is a negative regulator of urea cycle, thereby exerting a suppressive effect on growth of HCC tumors. Mechanistically, argininosuccinate lyase (ASL) is uncovered as the main target of taurine in repressing urea cycle of HCC cell lines. Furthermore, Fos proto-oncogene (FOS) functions as the transcription factor of ASL, which is significantly reduced upon taurine treatment. Physiologically, FOS-ASL axis is required for metabolic effects of taurine and contributes to growth of HCC tumors. Expression of ASL correlates with the inhibitory effect of taurine. Ultimately, synergistic blockade of glutaminolysis and urea cycle indicates that taurine is sufficient to substantially enhance the efficacy of the glutaminase GLS1 inhibitor in management of hepatocellular carcinoma. Collectively, these findings not only illustrate the metabolic mechanism of taurine in controlling growth of HCC tumors, but also create a promising route for utilization of taurine in clinic.