Expression and Clinical Significance of Protein Kinase RNA–Like Endoplasmic Reticulum Kinase and Phosphorylated Eukaryotic Initiation Factor 2&agr; in Pancreatic Ductal Adenocarcinoma

Abstract

Objectives Endoplasmic reticulum stress and subsequent phosphorylation of eukaryotic initiation factor 2&agr; (eIF2&agr;) by protein kinase R–like endoplasmic reticulum kinase (PERK) plays an important role in the development and chemoresistance of pancreatic ductal adenocarcinoma (PDAC). However, the expression and significance of phosphorylated eIF2&agr; (p-eIF2&agr;) and PERK in PDAC have not been examined. Methods We examined p-eIF2&agr; and PERK expression in 84 PDAC and paired normal pancreas samples by immunohistochemistry and Western blotting and correlated the results with clinicopathologic parameters and survival. Results Mean PERK H score was 140.8 in PDAC compared with 82.1 in normal pancreas (P < 0.001). High p-eIF2&agr; expression was present in 56% of PDACs versus 7.6% of normal pancreases (P < 0.001). High PERK and p-eIF2&agr; expression correlated with shorter overall survival (P = 0.048 and P = 0.03, respectively). By multivariate analysis, high p-eIF2&agr; (P = 0.01), positive margin (P = 0.002), and lymph node metastasis (P = 0.01) were independent prognosticators for survival. Conclusions The expression levels of PERK and p-eIF2&agr; are higher in PDAC than those in normal pancreas. High levels of PERK and p-eIF2&agr; are predictors of shorter survival in PDAC patients, suggesting that PERK and eIF2&agr; could be promising targets in PDAC.