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Protein disulphide isomerase inhibition as a potential cancer therapeutic strategy
Lauren E Powell1, Paul A Foster1,2
1Institute of Metabolism and Systems Research (IMSR), Medical and Dental School, University of Birmingham, Birmingham, UK.
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.
Insights
Protein disulphide isomerase (PDI) aids in protein folding and survival during cellular stress, showing promise as a therapeutic target for cancer treatment, particularly with inhibitors like PACMA 31.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Protein disulphide isomerase (PDI) enzymes are crucial for disulphide bond formation in the endoplasmic reticulum (ER).
- PDI plays a key role in maintaining ER proteostasis and is implicated in ER stress observed in diseases like cancer.
- The unfolded protein response (UPR) pathway, involving PDI, aims to alleviate ER stress and promote cell survival.
Purpose of the Study:
- To review the properties and functions of the PDI gene family.
- To explore the potential of PDI as a therapeutic target for cancer treatment.
- To highlight recent research on PDI inhibitors, such as PACMA 31, in cancer therapy.
Main Methods:
- Literature review of PDI functions in ER proteostasis and cancer.
- Analysis of PDI's role in the unfolded protein response (UPR) pathway.
- Examination of PDI inhibitors and their anti-cancer effects, specifically PACMA 31 in ovarian cancer.
Main Results:
- PDI is involved in ER stress and the UPR pathway, acting as both a chaperone and a regulator.
- PDI's pro-protective roles in cellular survival are evident.
- PDI inhibitors, including PACMA 31, show promising anti-cancer effects.
Conclusions:
- PDI is a significant factor in ER stress and cancer development.
- PDI's multifaceted roles make it a compelling therapeutic target for cancer treatment.
- Targeting PDI with specific inhibitors represents a potential strategy for novel cancer therapies.
