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

Alhammad, R; Khunchai, S; Tongmuang, N; Limjindaporn, T; Yenchitsomanus, P; Mutti, L; Krstic‑Demonacos, M; Demonacos, C

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.

Citation

Alhammad, R., Khunchai, S., Tongmuang, N., Limjindaporn, T., Yenchitsomanus, P., Mutti, L., …Demonacos, C. (2020). Protein disulfide isomerase A1 regulates breast cancer cell immunorecognition in a manner dependent on redox state. Oncology Reports, 44(6), 2406-2418. https://doi.org/10.3892/or.2020.7816

• Journal Article Type: Article
• Acceptance Date: Sep 1, 2020
• Online Publication Date: Oct 20, 2020
• Publication Date: Dec 1, 2020
• Deposit Date: Nov 2, 2020
• Publicly Available Date: Nov 2, 2020
• Journal: Oncology Reports
• Print ISSN: 1021-335X
• Electronic ISSN: 1791-2431
• Publisher: Spandidos Publications
• Volume: 44
• Issue: 6
• Pages: 2406-2418
• DOI: https://doi.org/10.3892/or.2020.7816
• Publisher URL: https://doi.org/10.3892/or.2020.7816
• Related Public URLs: http://www.spandidos-publications.com/or/
• Additional Information: Funders : Staff Development Fund, Naresuan University, Thailand Research Fund Royal Golden Jubilee PhD Program of Thailand;British Council Newton Fund;Center of Excellence on Medical Biotechnology (CEMB); Grant Number: CEMB-RP-005; Grant Number: IRN58W001; Grant Number: R016034008