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

## TL;DR

This study shows that Protein kinase R (PKR) promotes pancreatic cancer growth by regulating the cell cycle through GADD45A, suggesting PKR could be a new treatment target.

## Contribution

The study identifies a novel regulatory mechanism of PKR in pancreatic ductal adenocarcinoma via GADD45A.

## Key findings

- PKR inhibition reduces PDAC cell proliferation.
- GADD45A upregulation is linked to PKR suppression.
- GADD45A downregulation reverses the anti-proliferative effects of PKR knockdown.

## Abstract

Protein kinase R (PKR) functions both as a promoter and inhibitor in various cancers; however, its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. We investigated the role of PKR in PDAC. PKR expression in PDAC cell lines was assessed using real-time reverse transcriptase polymerase chain reaction and western blotting. The effect of PKR on cell proliferation was examined using MTS assay. To determine the mechanisms of PKR’s action on PDAC, RNA-sequencing analysis was performed, and the effects of PKR knockdown on cell cycle progression and apoptosis in PDAC cells were examined using flow cytometry. PDAC cell lines transfected with PKR-targeting short interfering RNAs or treated with PKR inhibitors exhibited significantly reduced proliferation. RNA-sequencing analysis revealed substantial upregulation of GADD45A expression upon inhibition of PKR expression. Following PKR silencing, cell cycle analysis showed marked accumulation of cells in G1 phase, consistent with the role of GADD45A as a cell cycle regulator. Proliferation inhibition caused by PKR knockdown was reversed by downregulation of GADD45A, suggesting that PKR and GADD45A interact to regulate PDAC cell growth. PKR promotes PDAC cell proliferation by modulating the cell cycle via regulation of GADD45A expression, demonstrating its potential as a therapeutic target for PDAC.

The online version contains supplementary material available at 10.1038/s41598-025-06213-4.