Functions and mechanisms of protein disulfide isomerase family in cancer emergence

Abstract

The endoplasmic reticulum (ER) is a multi-layered organelle that is essential for the synthesis, folding, and structural maturation of almost one-third of the cellular proteome. It houses several resident proteins for these functions including the 21 members of the protein disulfide isomerase (PDI) family. The signature of proteins belonging to this family is the presence of the thioredoxin domain which mediates the formation, and rearrangement of disulfide bonds of substrate proteins in the ER. This process is crucial not only for the proper folding of ER substrates but also for maintaining a balanced ER proteostasis. The inclusion of new PDI members with a wide variety of structural determinants, size and enzymatic activity has brought additional epitomes of how PDI functions. Notably, some of them do not carry the thioredoxin domain and others have roles outside the ER. This also reflects that PDIs may have specialized functions and their functions are not limited within the ER. Large-scale expression datasets of human clinical samples have identified that the expression of PDI members is elevated in pathophysiological states like cancer. Subsequent functional interrogations using structural, molecular, cellular, and animal models suggest that some PDI members support the survival, progression, and metastasis of several cancer types. Herein, we review recent research advances on PDIs, vis-à-vis their expression, functions, and molecular mechanisms in supporting cancer growth with special emphasis on the anterior gradient (AGR) subfamily. Last, we posit the relevance and therapeutic strategies in targeting the PDIs in cancer.

Fig. 1

Domain representation of PDI family members and family tree. A Schematic representation highlighting the a- and b-type domain arrangements, transmembrane domain (TM), and ER retention motifs of all 21 PDI family members. B Protein sequences of all 21 PDI family members were aligned using Clustal Omega and the corresponding matrix represented as a circular tree using the iTOL website (http://itol.embl.de/)

Fig. 2

The 3D structure of full-length human PDI/PDIA1 as predicted by AlphaFold (ID:AF-P07237-F1). The major domains are represented by different color surfaces. The active site containing the TRX motif, CGHC is colored in red

Fig. 3

Expression of PDI members in cancer landscape. The expression of PDIs is based on RNA-seq expression data extracted from the TCGA Pan Cancer Atlas

Fig. 4

Emerging roles of PDI protein family in cancer. Schematic representation summarizing the existing and emerging roles of PDI proteins in cancer. Although PDI proteins are crucial for ER function and integrity in normal cell physiology, in cancer cells however, PDI proteins can be translocated into different sub-cellular localizations such as the cytosol, cell surface and extracellular milieu. Existing data showed that these non-ER localizations of PDI proteins gain new functions in supporting cancer growth suggesting that the roles of PDI proteins go beyond the ER in diseased state like cancer