Protein disulphide isomerase inhibition as a potential cancer therapeutic strategy

Abstract

The protein disulphide isomerase (PDI) gene family is a large, diverse group of enzymes recognised for their roles in disulphide bond formation within the endoplasmic reticulum (ER). PDI therefore plays an important role in ER proteostasis, however, it also shows involvement in ER stress, a characteristic recognised in multiple disease states, including cancer. While the exact mechanisms by which PDI contributes to tumorigenesis are still not fully understood, PDI exhibits clear involvement in the unfolded protein response (UPR) pathway. The UPR acts to alleviate ER stress through the activation of ER chaperones, such as PDI, which act to refold misfolded proteins, promoting cell survival. PDI also acts as an upstream regulator of the UPR pathway, through redox regulation of UPR stress receptors. This demonstrates the pro‐protective roles of PDI and highlights PDI as a potential therapeutic target for cancer treatment. Recent research has explored the use of PDI inhibitors with PACMA 31 in particular, demonstrating promising anti‐cancer effects in ovarian cancer. This review discusses the properties and functions of PDI family members and focuses on their potential as a therapeutic target for cancer treatment.

Protein disulphide isomerase (PDI) is protective against several types of DNA damage, including that induced by amyotrophic lateral sclerosis-associated mutant TDP-43 in neuronal cells/ in vitro models

“…In addition, a link between PDI and DNA damage in relation to cancer was previously postulated. Accumulating evidence suggests that PDI is involved in the growth, metastasis, and survival of multiple types of cancer cells [78,79], which was associated with DNA damage [80]. Our findings revealing a novel function of PDI in response to DNA damage in the nucleus are therefore consistent with earlier studies describing PDI family members in this location.…”

Bacitracin and Rutin Regulate Tissue Factor Production in Inflammatory Monocytes and Acute Myeloid Leukemia Blasts

“…Rutin has higher specificity for PDI than bacitracin, but this flavonoid also targets other thiol isomerases, such as ERp5, ERp57, thioredoxin and thioredoxin reductase [67]. Although experiments using the inhibitory monoclonal antibody RL90 support a role of extracellular PDI in the regulation of TF production in THP1 cells (Figure S8A), downregulation of cellular PDI expression or use of newer-generation PDI inhibitors with higher potency and specificity would be necessary to better differentiate between PDI and other thiol isomerases [76].…”

ERp57/PDIA3: new insight

“…The members of this family are characterized by thioredoxin-like domains containing one or more active sites [ 1 ], with the canonical Cys–X–X–Cys sequence. Phylogenetic analysis of the human PDI family and subfamilies revealed a high correlation among the members along with an evident evolutionary divergence [ 2 ]. PDIs are involved in protein folding, catalyzing the formation and remodeling of disulfide bonds, and are mainly located in the endoplasmic reticulum (ER).…”

“…The human PDI family members display, beyond the presence of a thioredoxin-like domain, considerable differences in length and domain arrangement [ 2 ]. The first identified member of this protein family is PDIA1 (prolyl 4-hydroxylase subunit beta, P4HB gene), and it is structurally characterized by two thioredoxin-like active domains (a, a′), two substrate-binding domains (b, b′) with a hydrophobic pocket in the b′ domain, a linker sequence between the b′ and the a′ domains, and a C-terminal extended domain.…”

“…The two PDI members, PDIA1 and ERp57/PDIA3, have considerable overlap in their whole protein structure, but their differences are due to their different evidenced cellular biochemical roles in cellular homeostasis. For instance, PDIA1 catalyzes oxidative folding of non-glycoproteins via binding to the hydrophobic pocket of the b′ domain, while ERp57/PDIA3 promotes oxidative folding of glycoproteins selectively in concert with lectin chaperones calnexin and calreticulin [ 2 , 6 , 7 ]. Moreover, their enzymatic activity varies due to their differing redox potentials [ 8 ].…”