Malignant ascites supernatant enhances the proliferation of gastric cancer cells partially via the upregulation of asparagine synthetase.

Abstract

Malignant ascites (MA) is a common manifestation of advanced gastric cancer (GC) with peritoneal metastasis (PM), which usually indicates a poor prognosis. The present study aimed to explore the effects of MA, a unique microenvironment of PM, on the proliferation of cancer cells and investigate the underlying mechanisms. Ex vivo experiments demonstrated that GC cells treated with MA exhibited enhanced proliferation. RNA sequencing indicated that asparagine synthetase (ASNS) was one of the differentially expressed genes in GC cells following incubation with MAs. Furthermore, the present study suggested that MA induced an upregulation of ASNS expression and the stimulatory effect of MA on cancer cell proliferation was alleviated upon ASNS downregulation. Activating transcription factor 4 (ATF4), a pivotal transcription factor regulating ASNS, was upregulated when cells were treated with MA supernatant. After ATF4 knockdown, the proliferation of MA-treated GC cells and the expression of ASNS decreased. In addition, the decline in the proliferation of the ATF4-downregulated AGS GC cell line was rescued by ASNS upregulation. The findings indicated that MA could promote the proliferation of GC cells via activation of the ATF4-ASNS axis. Hence, it may be a potential target for treating GC with PM and MA.