A novel AGTPBP1-ERK/MYLK network mediates pancreatic cancer progression.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with dismal prognosis, driven by limited early detection and rapid metastatic progression. Although ATP/GTP binding protein 1 (AGTPBP1) is frequently overexpressed in PDAC, its mechanistic role in PDAC progression remains undefined. This study demonstrates that AGTPBP1 functions as a critical oncogenic driver of PDAC by promoting proliferation and migration in PANC-1 and AsPC-1 cells. Gain-of-function experiments showed that AGTPBP1 overexpression significantly increased both mRNA and protein levels, accelerating cell growth, colony formation, wound closure, and Transwell migration. Mechanistically, AGTPBP1 activated the MAPK/ERK pathway through elevated ERK1/2 phosphorylation, and pharmacological inhibition of ERK phosphorylation using PD98059 abrogated both ERK phosphorylation and AGTPBP1-driven phenotypes, establishing ERK as an essential mediator. Furthermore, AGTPBP1 modulated MYLK expression: overexpression increased while knockdown decreased MYLK mRNA and protein levels, and rescue experiments restored MYLK, confirming causality. Immunohistochemistry revealed co-elevation of AGTPBP1 and MYLK in PDAC compared to adjacent normal tissues. Notably, ERK signaling modulated MYLK activity (phosphorylated MYLK) without altering MYLK expression, indicating that AGTPBP1 regulates MYLK at the transcriptional level, whereas ERK controls its post-translational activity. Collectively, AGTPBP1 promotes PDAC progression through a dual mechanism involving ERK-dependent proliferative signaling and ERK-independent MYLK upregulation, positioning both molecules as potential therapeutic targets.