Protein disulfide isomerase A1 regulates breast cancer cell immunorecognition in a manner dependent on redox state

Alhammad,Rashed; Khunchai,Sasiprapa; Tongmuang,Nopprarat; Limjindaporn,Thawornchai; Yenchitsomanus,Pa‑Thai; Mutti,Luciano; Krstic‑Demonacos,Marija; Demonacos,Constantinos

doi:10.3892/or.2020.7816

Protein disulfide isomerase A1 regulates breast cancer cell immunorecognition in a manner dependent on redox state

Authors:
- Rashed Alhammad
- Sasiprapa Khunchai
- Nopprarat Tongmuang
- Thawornchai Limjindaporn
- Pa‑Thai Yenchitsomanus
- Luciano Mutti
- Marija Krstic‑Demonacos
- Constantinos Demonacos
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Affiliations: Faculty of Biology Medicine and Health, School of Health Sciences, Division of Pharmacy and Optometry, University of Manchester, Manchester M13 9PT, UK, Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand, Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA, University of Salford, School of Science, Engineering and Environment, Salford M5 4WT, UK
Published online on: October 20, 2020 https://doi.org/10.3892/or.2020.7816
Pages: 2406-2418
Copyright: © Alhammad et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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