Increasing Stress to Induce Apoptosis in Pancreatic Cancer via the Unfolded Protein Response (UPR)

• Type of Material: Article
• Authors: Gehan Botrus, Emory University; Richard M Miller, HonorHealth Research and Innovation Institute; Pedro Luiz Serrano Uson Jr, Hospital Israelita Albert Einstein; Geoffrey Kannan, LabCorp; Haiyong Han, Translational Genomics Research Institute (TGen); Daniel D Von Hoff, Translational Genomics Research Institute (TGen)
• Language: English
• Date: 2023-01-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/ijms24010577
• Title of Journal or Parent Work: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• Volume: 24
• Issue: 1
• Grant/Funding Information: This research received no external funding.
• Keywords: Physical Sciences; DEATH RECEPTOR 5; DRUG; MONOCLONAL-ANTIBODY; GEMCITABINE; endoplasmic reticulum (ER) stress; TO-DUCTAL METAPLASIA; Chemistry, Multidisciplinary; Science & Technology; Chemistry; TIGATUZUMAB; pancreatic cancer; PHASE-I TRIAL; unfolded protein response (UPR); Life Sciences & Biomedicine; ENDOPLASMIC-RETICULUM STRESS; ER STRESS; Biochemistry & Molecular Biology; RISK; apoptosis
• Research Categories: Health Sciences, Oncology

Abstract

High rates of cell proliferation and protein synthesis in pancreatic cancer are among many factors leading to endoplasmic reticulum (ER) stress. To restore cellular homeostasis, the unfolded protein response (UPR) activates as an adaptive mechanism through either the IRE1 (Formula presented.), PERK, or ATF6 pathways to reduce the translational load and process unfolded proteins, thus enabling tumor cells to proliferate. Under severe and prolonged ER stress, however, the UPR may promote adaptation, senescence, or apoptosis under these same pathways if homeostasis is not restored. In this review, we present evidence that high levels of ER stress and UPR activation are present in pancreatic cancer. We detail the mechanisms by which compounds activate one or many of the three arms of the UPR and effectuate downstream apoptosis and examine available data on the pre-clinical and clinical-phase ER stress inducers with the potential for anti-tumor efficacy in pancreatic cancer. Finally, we hypothesize a potential new approach to targeting pancreatic cancer by increasing levels of ER stress and UPR activation to incite apoptotic cell death.