GRP78 Is a Targetable Receptor on Cancer and Stromal Cells

Araujo, Nathalia; Hebbar, Nikhil; Rangnekar, Vivek M.

doi:10.1016/j.ebiom.2018.06.030

Cited by 25 publications

(18 citation statements)

References 10 publications

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“…D(KLAKLAK)2 after internalization disrupts mitochondrial membrane permeability and thus kills the cell [ 102 ]. BMTP78 induced dose-dependent cytotoxicity in human leukemia and lymphoma cell lines and acute myeloid leukemia patients [ 103 , 104 ]. Additionally, the GRP78 receptor/BMTP78 system was used to image breast tumors accurately.…”

Section: Grp78 Targeting Strategiesmentioning

confidence: 99%

GRP78 targeting: Hitting two birds with a stone

et al. 2020

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Background Glucose regulating protein 78 (GRP78) is one member of the Heat Shock Protein family of chaperone proteins (HSPA5) found in eukaryotes. It acts as the master of the Unfolded Protein Response (UPR) process in the lumen of the Endoplasmic Reticulum (ER). Scope Under the stress of unfolded proteins, GRP78 binds to the unfolded proteins to prevent misfolding, while under the load of the unfolded protein, it drives the cell to autophagy or apoptosis. Several attempts reported the overexpression of GRP78 on the cell membrane of cancer cells and cells infected with viruses or fungi. Major conclusions Cell-surface GRP78 is used as a cancer cell target in previous studies. Additionally, GRP78 is used as a drug target to stop the progression of cancer cells by different compounds, including peptides, antibodies, and some natural compounds. Additionally, it can be used as a protein target to reduce the infectivity of different viruses, including the pandemic SARS-CoV-2. Besides, GRP78 targeting is used in diagnosis and imaging modalities using radionuclides. General significance This review summarizes the various attempts that used GRP78 both in therapy (fighting cancer, viral and fungal infections) and diagnosis (imaging).

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Section: Grp78 Targeting Strategiesmentioning

confidence: 99%

GRP78 targeting: Hitting two birds with a stone

et al. 2020

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“…In recent years, the critical role of cell surface and secreted GRP78 in the tumor microenvironment, and its potential as a target in anti-cancer therapies, have become well-recognized [ 101 ]. For example, GRP78 is preferentially present on the surface of cancer cells, where it collaborates with other surface proteins to mediate anti-apoptotic and proliferative signaling [ 102 ].…”

Section: Secretion Of Ca 2+ -Binding Er Chaperomentioning

confidence: 99%

ER Stress-Induced Secretion of Proteins and Their Extracellular Functions in the Heart

Meyer

Doroudgar

2020

Cells

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Endoplasmic reticulum (ER) stress is a result of conditions that imbalance protein homeostasis or proteostasis at the ER, for example ischemia, and is a common event in various human pathologies, including the diseased heart. Cardiac integrity and function depend on the active secretion of mature proteins from a variety of cell types in the heart, a process that requires an intact ER environment for efficient protein folding and trafficking to the secretory pathway. As a consequence of ER stress, most protein secretion by the ER secretory pathway is decreased. Strikingly, there is a select group of proteins that are secreted in greater quantities during ER stress. ER stress resulting from the dysregulation of ER Ca2+ levels, for instance, stimulates the secretion of Ca2+-binding ER chaperones, especially GRP78, GRP94, calreticulin, and mesencephalic astrocyte-derived neurotrophic factor (MANF), which play a multitude of roles outside the cell, strongly depending on the cell type and tissue. Here we review current insights in ER stress-induced secretion of proteins, particularly from the heart, and highlight the extracellular functions of these proteins, ranging from the augmentation of cardiac cell viability to the modulation of pro- and anti-apoptotic, oncogenic, and immune-stimulatory cell signaling, cell invasion, extracellular proteostasis, and more. Many of the roles of ER stress-induced protein secretion remain to be explored in the heart. This article is part of a special issue entitled “The Role of Proteostasis Derailment in Cardiac Diseases.”

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“…Accordingly, the MDAMB231 cell line, which expresses lower levels of CREB3L1 at baseline, has more aggressive and metastatic features than other cell lines (29). The MDAMB468 cells which also express lower levels of CREB3L1 at baseline are highly proliferative with high Ki67 (37). In our experiments, the administration of chemotherapy (doxorubicin/paclitaxel) induced a significant increase in CREB3L1 protein expression in TNBC cell lines but not in ER positive or HER2-neu positive cell lines.…”

Section: Discussionmentioning

confidence: 48%

“…To confirm that the activation of CREB3L1 was mediated through the UPR pathway, we examined the correlation between CREB3L1 expression in each subtype with the expression of the key UPR molecule, GRP78, focusing on cell-surface GRP78 ( 38 ). The results demonstrated a significant increase in the expression of both cell-surface GRP78 and CREB3L1 in response to doxorubicin and paclitaxel specifically in the TNBC cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…Western blot analysis of MDAMB231 cells after doxorubicin or paclitaxel treatment disclosed a cleaved (activated) form of CREB3L1, apparently induced by the chemotherapy according to our collective results. Activated CREB3L1 functions as a transcription factor, affecting responsive elements of the endoplasmic reticulum and cyclic AMP to increase GRP78 expression ( 24 ), thereby stimulating GRP78 translocation to the cell surface ( 21 , 38 , 42 ). In the present study, only MDAMB231 and MDAMB468 cells, which showed a higher expression of cell-surface GRP78 and nuclear CREB3L1 in response to chemotherapy, exhibited a significantly reduced migratory profile.…”

Section: Discussionmentioning

confidence: 99%

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Chemotherapy Controls Metastasis Through Stimulatory Effects on GRP78 and Its Transcription Factor CREB3L1

et al. 2020

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To achieve a cure for metastatic breast cancer, further understanding of molecular drivers of the metastatic cascade is essential. Currently, chemotherapy regimens include doxorubicin and paclitaxel which act in part by inducing the unfolded protein response (UPR). The master regulator of the UPR, glucose regulated protein 78 (GRP78), localizes on the surface of tumor cells and is associated with metastatic disease. Cyclic AMP responsive element binding protein 3-like 1 (CREB3L1), a member of the UPR, is a breast cancer metastasis suppressor that acts on cyclic AMP to promote the expression of target genes including GRP78. The aim of the present study was to evaluate the effects of chemotherapy on CREB3L1 and cell-surface GRP78 expression and its association with the development of breast cancer metastasis. For this purpose, we use breast cancer cells migration in vitro assays and an in vivo metastatic mouse model. The results showed that chemotherapy activated CREB3L1 and enhanced cell-surface GRP78 expression specifically in triple-negative breast cancer cells (TNBC), reducing their migration and metastatic potential. CREB3L1 knockout (KO) in the triple negative MDAMB231 cell line using CRISPR/Cas9 technology led to inhibition of GRP78 expression and abrogation of the CREB3L1 metastatic suppression function. Inoculation of CREB3L1-KO MDAMB231 cells into a mouse metastatic model induced a massive metastatic profile which chemotherapy failed to prevent. These findings elucidate a potential pathway to the development of a novel treatment strategy for metastatic TNBC based on modulating CREB3L1 and cell-surface GRP78 expression by chemotherapy and GRP78-targeted drugs.

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GRP78 Is a Targetable Receptor on Cancer and Stromal Cells

Cited by 25 publications

References 10 publications

GRP78 targeting: Hitting two birds with a stone

GRP78 targeting: Hitting two birds with a stone

ER Stress-Induced Secretion of Proteins and Their Extracellular Functions in the Heart

Chemotherapy Controls Metastasis Through Stimulatory Effects on GRP78 and Its Transcription Factor CREB3L1

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