Agmatinase Facilitates Gastric Cancer Tumorigenesis Through PI3K/AKT-Mediated Enhancement of Proliferation, Invasion, and Stemness.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, and the molecular mechanisms driving its progression are incompletely understood. Agmatinase (AGMAT) has recently emerged as a candidate oncogene in several malignancies; however, its functional role in GC has not been characterized. In this study, we investigated AGMAT's role in GC, focusing on its effects on cell proliferation, invasion, stemness, and the underlying signaling mechanisms. Using GC cell lines AGS and HGC-27, we demonstrate that AGMAT overexpression promotes proliferation and invasion of GC cells and enhances sphere formation, a hallmark of cancer stem-like properties. Conversely, AGMAT knockdown via shRNA markedly suppressed cell proliferative, invasive, and sphere-forming capacities. Mechanistically, AGMAT activates the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, and pharmacological reactivation of this pathway using 740 Y-P rescued the proliferative, invasive, and stemness deficits caused by AGMAT depletion. In vivo studies using nude mice further corroborated our in vitro findings; AGMAT silencing led to a significant reduction in tumor volume and weight, accompanied by decreased expression of the proliferation marker Ki-67 and the stemness markers octamer-binding transcription factor 4 (OCT4) and SRY-box transcription factor 2 (SOX2) in AGMAT-silenced tumors. Furthermore, analysis of The Cancer Genome Atlas (TCGA) data revealed a correlation between elevated AGMAT expression and poor patient prognosis, reinforcing AGMAT's clinical significance in GC progression and patient outcomes. Collectively, our findings identify AGMAT as a novel oncogene that promotes GC cell proliferation, invasion, and stemness through PI3K/AKT pathway activation. These results suggest that AGMAT may serve as a potential therapeutic target and prognostic biomarker for GC.