ASS1 enhances anoikis resistance via AMPK/CPT1A-mediated fatty acid metabolism in ovarian cancer

Metastasis is the leading cause of death in ovarian carcinoma (OC), whereas anoikis resistance is a critical step for the survival of the detached OC cells. Despite extensive research, targeting anoikis resistance remains a challenge. Here, we first identified that argininosuccinate synthase 1 (ASS1), a key enzyme in urea cycle markedly upregulated in OC cells of detached culture, is associated with increased anoikis resistance and metastasis. Disruption of the AMP/ATP balance by overexpressing ASS1 activates AMPK and the downstream factor CPT1A. Then, we further found that ASS1 enhances FAO, leading to higher ATP generation and lipid utilization. Inhibition of CPT1A reverses the ASS1-induced FAO, which interrupts the AMP/ATP balance and the activation of AMPK. These results extend ASS1's relevance beyond nitrogen and fatty acid metabolisms, and may provide some new insights into OC metabolism and represent a shift from traditional views. In conclusion, our study reveals a mechanism that the ASS1/AMPK/CPT1A axis is crucial for anoikis resistance and metastasis, which may open up a new avenue for the intervention of OC.