HRI-mediated translational repression reduces proteotoxicity and sensitivity to bortezomib in human pancreatic cancer cells

• Published in: Oncogene Vol. 37; no. 32; pp. 4413 - 4427
• Main Authors: White, Matthew C., Schroeder, Rebecca D., Zhu, Keyi, Xiong, Katherine, McConkey, David J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2018; Nature Publishing Group
• Subjects: 13; 13/2; 13/89; 13/95; 14; 631/67/2329; 631/80/474/582; 631/80/82/23; Antineoplastic agents; Apoptosis; Bortezomib; Bortezomib - pharmacology; Cancer cells; Cell Biology; Cell death; Cell Death - drug effects; Cell Death - genetics; Cell Line, Tumor; Development and progression; Displays (Marketing); Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Drug therapy; Enzyme inhibitors; Enzyme regulation; Eukaryotic Initiation Factor-2 - genetics; Genetic aspects; Health aspects; Heme; Human Genetics; Humans; Internal Medicine; Kinases; Medicine; Medicine & Public Health; Molecular modelling; Oncology; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Patient outcomes; Phosphorylation; Phosphorylation - drug effects; Phosphorylation - genetics; Proteasome inhibitors; Proteasome Inhibitors - pharmacology; Protein Biosynthesis - drug effects; Protein Biosynthesis - genetics; Reactive oxygen species; Reactive Oxygen Species - metabolism; Targeted cancer therapy; Therapeutic applications; Translation; Tumor cell lines
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0227-y

Human cancer cells display extensive heterogeneity in their sensitivities to the proteasome inhibitor bortezomib (Velcade). The molecular mechanisms underlying this heterogeneity remain unclear, and strategies to overcome resistance are limited. Here, we discover that inherent differences in eIF2α phosphorylation among a panel of ten human pancreatic cancer cell lines significantly impacts bortezomib sensitivity, and implicate the HRI (heme-regulated inhibitor) eIF2α kinase as a novel therapeutic target. Within our panel, we identified a subset of cell lines with defective induction of eIF2α phosphorylation, conferring a high degree of sensitivity to bortezomib. These bortezomib-sensitive cells exhibited impaired translation attenuation followed by toxic accumulation of protein aggregates and reactive oxygen species (ROS), whereas the bortezomib-resistant cell lines displayed increased phosphorylation of eIF2α, decreased translation, few protein aggregates, and minimal ROS production. Importantly, we identified HRI as the primary bortezomib-activated eIF2α kinase, and demonstrated that HRI knockdown promoted cell death in the bortezomib-resistant cells. Overall, our data implicate inducible HRI-mediated phosphorylation of eIF2α as a central cytoprotective mechanism following exposure to bortezomib and provide proof-of-concept for the development of HRI inhibitors to overcome proteasome inhibitor resistance.