Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jan 15, 2022; 14(1): 38-54
Published online Jan 15, 2022. doi: 10.4251/wjgo.v14.i1.38
Proteasome regulators in pancreatic cancer
Nirosha J Murugan, Ioannis A Voutsadakis
Nirosha J Murugan, Department of Biology, Algoma University, Sault Sainte Marie P6A3T6, ON, Canada
Ioannis A Voutsadakis, Department of Medical Oncology, Sault Area Hospital, Sault Sainte Marie P6A3T6, ON, Canada
Author contributions: Voutsadakis IA conceived and designed the study, both authors reviewed the literature, wrote, revised and approved the manuscript.
Conflict-of-interest statement: The authors declare no conflict of interest regarding this manuscript.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Ioannis A Voutsadakis, MD, PhD, Associate Professor, Doctor, Department of Medical Oncology, Sault Area Hospital, 750 Great Northern Road, Sault Sainte Marie P6A3T6, ON, Canada.
Received: February 23, 2021
Peer-review started: February 23, 2021
First decision: March 29, 2021
Revised: April 14, 2021
Accepted: December 2, 2021
Article in press: December 2, 2021
Published online: January 15, 2022

Pancreatic adenocarcinoma is one of the most lethal cancers with rising incidence. Despite progress in its treatment, with the introduction of more effective chemotherapy regimens in the last decade, prognosis of metastatic disease remains inferior to other cancers with long term survival being the exception. Molecular characterization of pancreatic cancer has elucidated the landscape of the disease and has revealed common lesions that contribute to pancreatic carcinogenesis. Regulation of proteostasis is critical in cancers due to increased protein turnover required to support the intense metabolism of cancer cells. The proteasome is an integral part of this regulation and is regulated, in its turn, by key transcription factors, which induce transcription of proteasome structural units. These include FOXO family transcription factors, NFE2L2, hHSF1 and hHSF2, and NF-Y. Networks that encompass proteasome regulators and transduction pathways dysregulated in pancreatic cancer such as the KRAS/ BRAF/MAPK and the Transforming growth factor beta/SMAD pathway contribute to pancreatic cancer progression. This review discusses the proteasome and its transcription factors within the pancreatic cancer cellular micro-environment. We also consider the role of stemness in carcinogenesis and the use of proteasome inhibitors as therapeutic agents.

Keywords: Pancreatic adenocarcinoma, Proteasome, Transcription factors, Regulation, Unfolded protein response, Cancer stem cells

Core Tip: Pancreatic adenocarcinoma is a gastrointestinal cancer with high incidence and bleak outcomes. The molecular pathways involved in the pathogenesis of the disease have been increasingly clarified in recent years. This article reviews the role of proteostasis regulation through the proteasome in pancreatic cancer. Major molecular pathways affected in pancreatic cancer closely interconnect with regulators of the proteasome.