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Protein disulfide isomerase family mediated redox regulation in cancer.

ABSTRACT: Protein disulfide isomerase (PDI) and its superfamilies are mainly endoplasmic reticulum (ER) resident proteins with essential roles in maintaining cellular homeostasis, via thiol oxidation/reduction cycles, chaperoning, and isomerization of client proteins. Since PDIs play an important role in ER homeostasis, their upregulation supports cell survival and they are found in a variety of cancer types. Despite the fact that the importance of PDI to tumorigenesis remains to be understood, it is emerging as a new therapeutic target in cancer. During the past decade, several PDI inhibitors has been developed and commercialized, but none has been approved for clinical use. In this review, we discuss the properties and redox regulation of PDIs within the ER and provide an overview of the last 5 years of advances regarding PDI inhibitors.

SUBMITTER: Ye ZW

PROVIDER: S-EPMC10586477 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Protein disulfide isomerase family mediated redox regulation in cancer.

Ye Zhi-Wei ZW Zhang Jie J Aslam Muhammad M Blumental-Perry Anna A Tew Kenneth D KD Townsend Danyelle M DM

Advances in cancer research 20230718

Protein disulfide isomerase (PDI) and its superfamilies are mainly endoplasmic reticulum (ER) resident proteins with essential roles in maintaining cellular homeostasis, via thiol oxidation/reduction cycles, chaperoning, and isomerization of client proteins. Since PDIs play an important role in ER homeostasis, their upregulation supports cell survival and they are found in a variety of cancer types. Despite the fact that the importance of PDI to tumorigenesis remains to be understood, it is emer ...[more]

PMID: 37704292

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Project description:Oxidoreductase protein disulphide isomerases (PDI) are involved in the regulation of a variety of biological processes including the modulation of endoplasmic reticulum (ER) stress, unfolded protein response (UPR), ER‑mitochondria communication and the balance between pro‑survival and pro‑death pathways. In the current study the role of the PDIA1 family member in breast carcinogenesis was investigated by measuring ROS generation, mitochondrial membrane disruption, ATP production and HLA‑G protein levels on the surface of the cellular membrane in the presence or absence of PDIA1. The results showed that this enzyme exerted pro‑apoptotic effects in estrogen receptor (ERα)‑positive breast cancer MCF‑7 and pro‑survival in triple negative breast cancer (TNBC) MDA‑MB‑231 cells. ATP generation was upregulated in PDIA1‑silenced MCF‑7 cells and downregulated in PDIA1‑silenced MDA‑MB‑231 cells in a manner dependent on the cellular redox status. Furthermore, MCF‑7 and MDA‑MB‑231 cells in the presence of PDIA1 expressed higher surface levels of the non‑classical human leukocyte antigen (HLA‑G) under oxidative stress conditions. Evaluation of the METABRIC datasets showed that low PDIA1 and high HLA‑G mRNA expression levels correlated with longer survival in both ERα‑positive and ERα‑negative stage 2 breast cancer patients. In addition, analysis of the PDIA1 vs. the HLA‑G mRNA ratio in the subgroup of the living stage 2 breast cancer patients exhibiting low PDIA1 and high HLA‑G mRNA levels revealed that the longer the survival time of the ratio was high PDIA1 and low HLA‑G mRNA and occurred predominantly in ERα‑positive breast cancer patients whereas in the same subgroup of the ERα‑negative breast cancer mainly this ratio was low PDIA1 and high HLA‑G mRNA. Taken together these results provide evidence supporting the view that PDIA1 is linked to several hallmarks of breast cancer pathways including the process of antigen processing and presentation and tumor immunorecognition.

Dataset Information

Protein disulfide isomerase family mediated redox regulation in cancer.

Publications

Protein disulfide isomerase family mediated redox regulation in cancer.

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