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

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.

Protein disulfide isomerase A1‑associated pathways in the development of stratified breast cancer therapies

“…siRNA transfection. Concentration of 5 µM of the siGENOME PDIA1 siRNA and 5 µM of the siGENOME non-targeting siRNA pool was added to each well containing 2x10 5 cells in DMEM and incubated for 72 h according to the suppliers' instructions (Dharmacon, UK) as described previously (4). The sequences of the siRNAs used are indicated as follows: siGE-NOME PDIA1-targeting siRNA pool: ACA GGA CGG UCA UUG AUU A, GGA CGG UCA UUG AUU ACA A, CCA AGAG UGU GUC UGA CUA, and CAGAGAGGAUCACAGAGUU; siGENOME non-targeting (scramble) siRNA pool: UAG CGA CUA AAC ACA UCA A, UAA GGC UAU GAA GAG AUA C, AUG UAU UGG CCU GUA UUA G, and AUG AAC GUG AAU UGC UCA A.…”

“…The PDI family member prolyl 4-hydroxylase β (P4HB, also known as PDIA1) functions as a chaperone that assists protein folding by inhibiting the aggregation of partially folded or damaged polypeptides (6). Recent findings have implicated PDIA1 in the processes of antigen processing and presentation, immunomodulation and tumor immunorecognition (4,(7)(8)(9).…”

“…Protein disulfide isomerases (PDIs) are involved in a wide range of biological pathways as mediators of oxidative folding in the endoplasmic reticulum ( 1 , 2 ), in the formation, breakage, and rearrangement of disulfide bonds ( 1 , 3 ), and in the regulation of apoptosis, exerting both pro-apoptotic and pro-survival effects ( 4 , 5 ). The PDI family member prolyl 4-hydroxylase β (P4HB, also known as PDIA1) functions as a chaperone that assists protein folding by inhibiting the aggregation of partially folded or damaged polypeptides ( 6 ).…”

“…PDIA1 has been shown to play an important role in various stages of carcinogenesis in a wide variety of cancers, being involved in the early stages of carcinogenesis possibly by contributing to the management of misfolded and non-functional proteins ( 5 ) as well as in the evasion of the immunosurveillance ( 4 ). Evidence has been presented that PDI family members are involved in the proliferation and metastasis of brain, kidney, and lung cancers ( 10 , 11 ).…”

SARS-CoV-2 and Other Respiratory Viruses: What Does Oxidative Stress Have to Do with It?

“…Protein disulfide isomerases (PDIs) constitute a superfamily of redox chaperones that participate in important cellular redox state processes, such as the modulation of cellular oxidative stress mediating homeostasis of the antioxidant glutathione [ 157 ], modulation of endoplasmic reticulum stress, the unfolded protein response, communication between endoplasmic reticulum and mitochondria, and the balance between cell proliferation and apoptosis [ 158 ]. A pulmonary fibrosis study showed that a domain of PDI (TXNDC5) was highly upregulated in patients with idiopathic pulmonary fibrosis as well as a mouse model of this injury, suggesting that this protein could be a novel therapeutic target in the treatment of pulmonary fibrosis [ 159 ].…”