Abstract

Pancreatitis is a debilitating disease involving inflammation and fibrosis of the exocrine pancreas.
Recurrent or chronic forms of pancreatitis are a significant risk factor for pancreatic ductal adenocarcinoma. While genetic factors have been identified for both pathologies, environmental stresses play a
large role in their etiology. All cells have adapted mechanisms to handle acute environmental stress that
alters energy demands. A common pathway involved in the stress response involves endoplasmic reticulum stress and the unfolded protein response (UPR). While rapidly activated by many external
stressors, in the pancreas the UPR plays a fundamental biological role, likely due to the high protein
demands in acinar cells. Despite this, increased UPR activity is observed in response to acute injury or
following exposure to risk factors associated with pancreatitis and pancreatic cancer. Studies in animal
and cell cultures models show the importance of affecting the UPR in the context of both diseases, and
inhibitors have been developed for several specific mediators of the UPR. Given the importance of the
UPR to normal acinar cell function, efforts to affect the UPR in the context of disease must be able to
specifically target pathology vs. physiology. In this review, we highlight the importance of the UPR to
normal and pathological conditions of the exocrine pancreas. We discuss recent studies suggesting the
UPR may be involved in the initiation and progression of pancreatitis and PDAC, as well as contributing to
chemoresistance that occurs in pancreatic cancer. Finally, we discuss the potential of targeting the UPR
for treatment