Protein Kinase R regulates pancreatic ductal adenocarcinoma progression by modulating the cell cycle via GADD45A

Protein kinase R (PKR) functions both as a promoter and inhibitor in various cancers, yet its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study aimed to investigate the role of PKR in PDAC. PKR expression in PDAC cell lines was assessed using real-time reverse transcriptase polymerase chain reaction and western blot analysis. The MTS assay was employed to evaluate the effect of PKR on cell proliferation. To elucidate the underlying mechanisms of PKR's action on PDAC, RNA-sequencing (RNA-seq) analysis was performed, and flow cytometry was used to examine the effects of PKR knockdown on cell cycle progression and apoptosis in PDAC cells.　The results indicated that PDAC cell lines exhibited significantly reduced proliferation when transfected with PKR-targeting siRNAs or treated with PKR inhibitors. RNA-seq analysis revealed a substantial upregulation of GADD45A expression upon inhibition of PKR expression. Following PKR silencing, cell cycle analysis showed a marked accumulation of cells in the G1 phase, which is consistent with GADD45A's known role as a cell cycle regulator. Furthermore, the inhibition of proliferation caused by PKR knockdown was reversed by the downregulation of GADD45A, suggesting an interactive effect between PKR and GADD45A in regulating PDAC cell growth.　In conclusion, PKR promotes PDAC cell proliferation by modulating the cell cycle through the regulation of GADD45A expression. These findings suggest that PKR may serve as a potential novel therapeutic target for PDAC.