Significance: Diabetes has long been recognized as an independent risk factor for
cancer, but there is insufficient mechanistic understanding of
biological mediators that bridge two disorders together. Understanding the pathogenic association between diabetes and
cancer has become the focus of many studies, and findings are potentially valuable for the development of effective preventive or therapeutic strategies for both disorders. Recent Advances: A summary of literature reveals a possible connection between diabetes and
cancer through the family of
protein disulfide isomerase (PDI). Historical as well as the most recent findings on the structure, biochemistry, and biology of the PDI family were summarized in this review. Critical Issues: PDIs in general function as redox
enzymes and
protein chaperones to control the quality of
proteins by correcting or otherwise eliminating misfolded
proteins in conditions of oxidative stress and endoplasmic reticulum stress, respectively. However, individual members of the PDI family may contribute uniquely to the pathogenesis of diabetes and
cancer. Studies of exemplary members such as
protein disulfide isomerase-associated (PDIA) 1, PDIA6, and PDIA15 were reviewed to highlight their contributions in the pathogenesis of diabetes and
cancer and how they can be potential links bridging the two disorders through the cross talk of signaling pathways. Future Directions: Apparently ubiquitous presence of the PDIs creates difficulties and challenges for scientific community to develop targeted
therapeutics for the treatment of diabetes and
cancer simultaneously. Understanding molecular contribution of individual PDI in the context of specific disease may provide some insights into the development of mechanism-based target-directed
therapeutics. Antioxid. Redox Signal. 37, 1191-1205.