Argininosuccinate synthase 1 suppresses tumor progression through activation of PERK/eIF2?/ATF4/CHOP axis in hepatocellular carcinoma

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide, and liver cancer has increased in mortality due to because it was detected at an advanced stages patients with dysfunction, making HCC a lethal cancer. Accordingly, we aim new targets for drug discovery using tumor spheroids. Methods Our comparative proteomic analysis cells grown culture as monolayers (2D) spheroids (3D) revealed that argininosuccinate synthase 1 (ASS1) expression higher 3D than 2D upregulated endoplasmic reticulum (ER) stress responses. We investigated clinical value ASS1 Korean HCC. The mechanism underlying ASS1-mediated suppression improvement chemotherapy efficiency observed high content screening xenograft mouse model. Results Studies tissue from showed that, although low samples, levels were associated favorable overall survival patients. Here, found bidirectional interactions between ER responses HCC-derived multicellular can limit progression. overexpression effectively inhibited growth enhanced efficacy vitro vivo anti-HCC combination via activation PERK/eIF2?/ATF4/CHOP axis, but not dependent on status p53 arginine metabolism. Conclusions These results demonstrate critical functional roles metabolism–independent suppressor activity suggest upregulating these tumors potential strategy expression.