The Glucose-Regulated Protein78 (GRP78) in the Unfolded Protein Response (UPR) Pathway: A Potential Therapeutic Target for Breast Cancer

Abstract

Amongst all types of cancers, breast cancer is recognized as the most common cancer and a principal cause of morbidity and mortality in women. Endoplasmic reticulum (ER) stress pathways are primarily activated in cancer cells and activate a signaling network called the unfolded protein response (UPR). Many tumors, by activating the UPR pathway, allow to adapt and grow under stressful conditions. UPR is usually inactive in non-tumor cells, while it is active in tumor cells, so it is appropriate to develop new breast cancer therapies. A protein that regulates UPR is 78 KDa Glucose-Regulated Protein (GRP78). Usually, the GRP78 level in the cell is relatively low but increases significantly under stresses that affect the ER and calcium homeostasis, and increases resistance to chemotherapy. GRP78 drug suppressors could provide promising anticancer therapeutics. Therefore, understanding the molecular mechanism of GRP78 in cancer and identifying drugs that target GRP78 is essential for the treatment of breast cancer. In this review, we investigate the role of GRP78 in the pathogenesis of breast cancer.

Ginsenoside F4 Alleviates Skeletal Muscle Insulin Resistance by Regulating PTP1B in Type II Diabetes Mellitus

“…ER stress occurs when there is an imbalance between the demand and capacity for ER protein folding, resulting in the accumulation of misfolded proteins . In contrast, the unfolded protein response (UPR) is usually an important feature in the development of ERS and is mediated by three transmembrane ER proteins, that is, IRE-1, protein kinase RNA-like ER kinase, and activating transcription factor 6. – Under non-stress conditions, these proteins bind to GRP78, the main regulator of the UPR . When activated by stress, GRP78 dissociates from transmembrane ER proteins, leading to their activation .…”

“…36−39 Under non-stress conditions, these proteins bind to GRP78, the main regulator of the UPR. 40 When activated by stress, GRP78 dissociates from transmembrane ER proteins, leading to their activation. 41 It has been claimed that PTP1B enhances IRE-1 signaling in ER stress and activates downstream JNK phosphorylation, leading to IRS-1 protein serine phosphorylation and causing insulin resistance.…”

Unveiling the dark side of glucose-regulated protein 78 (GRP78) in cancers and other human pathology: a systematic review

“…GRP78 activates pro-survival pathways, such as the PI3K/AKT and MAPK/ERK signaling pathways, which promote cell survival and inhibit apoptosis. It also interacts with and stabilizes anti-apoptotic proteins, such as Bcl-2 family members, preventing the activation of apoptotic pathways (Kuang et al 2016 ; Kabakov and Gabai 2021 ; Dong et al 2011 ; Sadeghipour et al 2023 ) 5 Head and Neck Cancer Tumor progression, chemoresistance The progression, survival and chemo-resistance properties of head and neck cancer are attributed to GRP78. GRP78 promotes the survival of head and neck cancer cells by maintaining lysosomal activities through the help of MUL 1, one of E3 ubiquitin-protein ligases (MUL1-GRP78) (Kim et al 2018 ; Schneider et al 2022 ) 6 Prostate Cancer Androgen receptor signaling, cell survival GRP78 modulates androgen receptor signaling, promotes cell survival, and contributes to castration resistance in prostate cancer.…”

PLXNC1 interference alleviates the inflammatory injury, apoptosis and extracellular matrix degradation of IL-1β-exposed chondrocytes via suppressing GRP78 expression

“…GRP78 is a multi-functional protein which is primarily expressed in the lumen of the endoplasmic reticulum [ 10 , 11 ]. Existing evidence has proposed that GRP78 extensively participates in human malignancies and diseases via mediating endoplasmic reticulum stress and unfolded protein response as a molecular chaperone in endoplasmic reticulum [ 10 – 12 ]. Moreover, GRP78 expression is increased in cartilages as OA progresses [ 13 ] and GRP78 interference suppresses oxidative stress in chondrocytes [ 14 ].…”