Protein Disulfide Isomerases Function as the Missing Link Between Diabetes and Cancer

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.