Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential
Nature reviews. CancerPublished 24 March 2014Open access
Amy S. Lee
Citations618
SJR quartileQ1
SJR score24.38
SNIP11.13
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TL;DR
The glucose-regulated proteins are found and regulation are described, as well as their biological functions in cancer and promising agents that use or target the GRPs are developed, and their efficacy as anticancer therapeutics is discussed.
Abstract
The glucose-regulated proteins (GRPs) are stress-inducible chaperones that mostly reside in the endoplasmic reticulum or the mitochondria. Recent advances show that the GRPs have functions that are distinct from those of the related heat shock proteins, and they can be actively translocated to other cellular locations and assume novel functions that control signalling, proliferation, invasion, apoptosis, inflammation and immunity. Mouse models further identified their specific roles in development, tumorigenesis, metastasis and angiogenesis. This Review describes their discovery and regulation, as well as their biological functions in cancer. Promising agents that use or target the GRPs are being developed, and their efficacy as anticancer therapeutics is also discussed.
Keywords
MedicineBiochemistry, Genetics and Molecular Biology
Nature Reviews Molecular Cell BiologySignal integration in the endoplasmic reticulum unfolded protein response
6,283 Citations2007David Ron, Peter Walter
Nature Reviews Molecular Cell BiologyThe unfolded protein response: controlling cell fate decisions under ER stress and beyond
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Insight is provided into the regulatory mechanisms and signalling crosstalk of the three branches of the UPR, which are initiated by the stress sensors protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α) and activating transcription factor 6 (ATF6).
Molecular and Cellular BiologyXBP-1 Regulates a Subset of Endoplasmic Reticulum Resident Chaperone Genes in the Unfolded Protein Response
2,057 Citations2003Ann–Hwee Lee, Neal N. Iwakoshi +1 more
It is suggested that the IRE1/XBP-1 pathway is required for efficient protein folding, maturation, and degradation in the ER and imply the existence of subsets of UPR target genes as defined by their dependence on XBP- 1.
CellAutophagy Suppresses Tumorigenesis through Elimination of p62
1,707 Citations2009Robin Mathew, Cristina M. Karp +11 more
Defective autophagy is a mechanism for p62 upregulation commonly observed in human tumors that contributes directly to tumorigenesis likely by perturbing the signal transduction adaptor function of p62-controlling pathways critical for oncogenesis.
CellAn hsp70-like protein in the ER: Identity with the 78 kd glucose-regulated protein and immunoglobulin heavy chain binding protein
1,469 Citations1986Sean Munro, Hugh R.B. Pelham
A cDNA clone is characterized that encodes a protein related to the 70 kd heat shock protein, but is expressed in normal rat liver, and it is identical with two previously described proteins: GRP78, whose synthesis is induced by glucose starvation, and BiP, which is found bound to immunoglobulin heavy chains in pre-B cells.
Journal of Biological ChemistryIdentification of the cis-Acting Endoplasmic Reticulum Stress Response Element Responsible for Transcriptional Induction of Mammalian Glucose-regulated Proteins
1,244 Citations1998Hiderou Yoshida, Kyosuke Haze +3 more
The results suggest that, as in yeast, bZIP proteins are involved in mammalian UPR, acting through newly defined ERSE,acting through newlydefined ERSE.
Genes & DevelopmentIRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response
1,061 Citations2002Kyung‐Ho Lee, Witoon Tirasophon +7 more
It is proposed that nuclear- localized IRE1alpha and cytoplasmic-localized ATF6 signaling pathways merge through regulation of XBP1 activity to induce downstream gene expression.
CellTenets of PTEN Tumor Suppression
1,019 Citations2008Leonardo Salmena, Arkaitz Carracedo +1 more
This review discusses emerging modes of PTEN function and regulation, and speculates about how manipulation ofPTEN function could be used for cancer therapy.
CellTripartite Management of Unfolded Proteins in the Endoplasmic Reticulum
914 Citations2000Kazutoshi Mori
The cellular responses to the accumulation of unfolded proteins in the ER are much more extensive than previously recognized and will provide new insights into not only fundamental principles in cell biology but also the pathogenesis of diseases that result from problems in protein folding in theER.
The Journal of Cell BiologyPosttranslational association of immunoglobulin heavy chain binding protein with nascent heavy chains in nonsecreting and secreting hybridomas.
893 Citations1986D G Bole, Linda M. Hendershot +1 more
It is proposed that the association of BiP with Ig heavy chain precursors is a novel posttranslational processing event occurring in the endoplasmic reticulum and may prevent the premature escape and eventual secretion of incompletely assembled Ig molecules.
Cell Death and DifferentiationFrom acute ER stress to physiological roles of the Unfolded Protein Response
872 Citations2006Jun Wu, Randal J. Kaufman
There is a growing body of data that suggest that different subpathways of the UPR are required throughout the entire life of eucaryotic organisms, from regulation of differentiation to induction of apoptosis.
Cancer ResearchGRP78 Induction in Cancer: Therapeutic and Prognostic Implications
856 Citations2007Amy S. Lee
The recent discovery ofGRP78 on the cell surface of cancer cells but not in normal tissues suggests that targeted therapy against cancer via surface GRP78 may be feasible.
NatureImmunoglobulin heavy chain binding protein
852 Citations1983Ingrid G. Haas, Matthias Wabl
It is shown that the protein (which is term immunoglobulin heavy-chain binding protein, BiP) binds non-covalently to free IgH, but not to IgH associated with IgL.
NaturePTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention
816 Citations2006Jiwang Zhang, Justin C. Grindley +10 more
It is shown that inactivation of PTEN in bone marrow HSCs causes their short-term expansion, but long-term decline, primarily owing to an enhanced level of HSC activation.
Trends in Cell BiologyMAM: more than just a housekeeper
754 Citations2009Teruo Hayashi, Rosario Rizzuto +2 more
The MAM thus integrates signal transduction with metabolic pathways to regulate the communication and functional interactions between the ER and mitochondrion and enables highly efficient transmission of Ca(2+) from the ER to mitochondria to stimulate oxidative metabolism and, conversely, might enable the metabolically energized mitochondria
FEBS LettersER chaperones in mammalian development and human diseases
731 Citations2007Min Ni, Amy S. Lee
Many of the new insights are derived from recently constructed mouse models where the genes encoding the chaperones are genetically altered, providing invaluable tools for examining the physiological involvement of the ER chaperone in vivo.
Nature reviews. CancerThe role of the unfolded protein response in tumour development: friend or foe?
709 Citations2004Yanjun Ma, Linda M. Hendershot
Recent delineation of the components of this response indicate that it is uniquely poised to have a role in regulating the balance between cancer cell death, dormancy and aggressive growth, as well as altering the sensitivity of solid tumours to chemotherapeutic agents.
Journal of Biological ChemistryEndoplasmic Reticulum Chaperone Protein GRP78 Protects Cells from Apoptosis Induced by Topoisomerase Inhibitors
692 Citations2003Ramachandra K. Reddy, Changhui Mao +4 more
Evidence is provided that a subpopulation of GRP78 can exist as an ER transmembrane protein, as well as co-localize with caspase-7, as confirmed by fluorescence microscopy and this effect can be reversed by addition of dATP in a cell-free system.
Antioxidants and Redox SignalingRole of the Unfolded Protein Response Regulator GRP78/BiP in Development, Cancer, and Neurological Disorders
605 Citations2009Miao Wang, Shiuan Wey +3 more
The discovery of surface localization of GRP78 in cancer cells reveals potential novel function, interaction with cell-surface receptors, and possible therapeutic implications and mouse models reveal that GRP 78 controls maturation and secretion of neuronal factors for proper neural migration and offers neuroprotection.
Current Molecular MedicineStress Induction of GRP78/BiP and Its Role in Cancer
587 Citations2006Jianze Li, Amy S. Lee
The transcriptional regulation of Grp78, the molecular basis for the cytoprotective function of GRP78 and its role in cancer progression, drug resistance and potential future cancer therapy are summarized.
FEBS LettersCoupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78
573 Citations2002Rammohan V. Rao, Alyson Peel +8 more
A novel protective role for GRP78 is defined in preventing ER stress‐induced cell death and addition of (d)ATP dissociates this complex and may facilitate movement of caspase‐12 into the cytoplasm to set in motion the cytosolic component of the ER stress-induced apoptotic cascade.
OncogeneThe critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies
565 Citations2012B Luo, Amy S. Lee
P perturbance of ER homeostasis has critical roles in tumorigenesis, and therapeutic modulation of ER chaperones and/or UPR components presents potential antitumor treatments.
Biochemical JournalBeyond the endoplasmic reticulum: atypical GRP78 in cell viability, signalling and therapeutic targeting
534 Citations2011Min Ni, Yi Zhang +1 more
Cell-surface GRP78 has emerged as an important regulator of tumour cell signalling and viability as it forms complexes with a rapidly expanding repertoire of cell-surface protein partners, regulating proliferation, PI3K (phosphoinositide 3-kinase)/Akt signalling and cell viability.
Cancer ResearchThe Unfolded Protein Response Regulator GRP78/BiP as a Novel Target for Increasing Chemosensitivity in Malignant Gliomas
448 Citations2007Peter Pyrko, Axel H. Schönthal +3 more
The results identify a novel chemoresistance mechanism in malignant gliomas and show that combination of drugs capable of suppressing GRP78 with conventional agents such as temozolomide might represent a novel approach to eliminate residual tumor cells after surgery and increase the effectiveness of malignantglioma chemotherapy.
Cell Death and DifferentiationThe unfolded protein response regulator GRP78/BiP is required for endoplasmic reticulum integrity and stress-induced autophagy in mammalian cells
447 Citations2008Jiaxi Li, Min Ni +4 more
3-MA is uncovered as an inhibitor of UPR activation and GRP78 is established as a novel obligatory component of autophagy in mammalian cells.
ImmunityHeat Shock Protein gp96 Is a Master Chaperone for Toll-like Receptors and Is Important in the Innate Function of Macrophages
443 Citations2007Yi Yang, Bei Liu +5 more
It is demonstrated that gp96 is the master chaperone for TLRs and that macrophages, but not other myeloid cells, are the dominant source of proinflammatory cytokines during endotoxemia and Listeria infections.
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424 Citations2006Shengzhan Luo, Changhui Mao +2 more
Findings provide the first evidence that GRP78 is essential for embryonic cell growth and pluripotent cell survival.
Biochimica et Biophysica Acta (BBA) - Molecular Cell ResearchGRP94: An HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum
419 Citations2011Michał Marzec, Davide Eletto +1 more
Glucose-regulated protein 94 is the HSP90-like protein in the lumen of the endoplasmic reticulum and therefore it chaperones secreted and membrane proteins and the basis for this selectivity remains obscure.
Cancer CellCell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands
414 Citations2004Marco A. Arap, Johanna Lahdenranta +5 more
It is shown that GRP78 binding peptide motifs target tumor cells specifically in vivo and in human cancer specimens ex vivo, and synthetic chimeric peptides composed of GRP 78 binding motifs fused to a programmed cell death-inducing sequence can suppress tumor growth in xenograft and isogenic mouse models of prostate and breast cancer.
Journal of Cellular PhysiologyCultured animal cells exposed to amino acid analogues or puromycin rapidly synthesize several polypeptides
390 Citations1980Lawrence E. Hightower
In mammalian cells, the rate of accumulation of several polypeptides, which were similar in size to the avian proteins, sharply increased after canavanine treatment.
Cancer ResearchCritical Role of the Stress Chaperone GRP78/BiP in Tumor Proliferation, Survival, and Tumor Angiogenesis in Transgene-Induced Mammary Tumor Development
371 Citations2008Dezheng Dong, Min Ni +12 more
It is reported that Grp78 heterozygosity has no effect on organ development or antibody production but prolongs the latency period and significantly impedes tumor growth, establishing that a key UPR target GRP78 is preferably required for pathophysiologic conditions, such as tumor proliferation, survival, and angiogenesis.
NatureAB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP
368 Citations2006Adrienne W. Paton, Travis Beddoe +6 more
BiP is a master regulator of endoplasmic reticulum function, and its cleavage by subtilase cytotoxin represents a previously unknown trigger for cell death.
The International Journal of Biochemistry & Cell BiologyStructural and functional link between the mitochondrial network and the endoplasmic reticulum
366 Citations2009Carlotta Giorgi, Diego De Stefani +3 more
The basic principles of ER mitochondrial Ca(2+) transport, and the physiological/pathological role of this cross-talk are reviewed.
Breast Cancer Research and TreatmentOverexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions
332 Citations2000Patricia M. Fernández, Sana Tabbara +6 more
The results suggest that some breast tumors exhibit adverse microenvironment conditions that induce the overexpression of specific stress genes that may play a role in resistance to apoptosis and decreased chemotherapeutic efficacy.
Journal of Biological ChemistryCell Surface Relocalization of the Endoplasmic Reticulum Chaperone and Unfolded Protein Response Regulator GRP78/BiP
328 Citations2010Yi Zhang, Ren Liu +3 more
It is reported that ER stress actively promotes GRP78 localization on the cell surface, whereas ectopic expression ofGRP78 is also able to cause cell surface relocation in the absence of ER stress.
Cancer ResearchGRP78/BiP Inhibits Endoplasmic Reticulum BIK and Protects Human Breast Cancer Cells against Estrogen Starvation–Induced Apoptosis
303 Citations2007Yong Fu, Jianze Li +1 more
The results provide the first evidence that GRP78 confers resistance to estrogen starvation-induced apoptosis in human breast cancer cells via a novel mechanism mediated by BIK and suggest thatGRP78 expression level in the tumor cells may serve as a prognostic marker for responsiveness to hormonal therapy based on estrogen starvation and that combination therapy targeting GRP 78 may enhance efficacy and reduce resistance.
Journal of Biological ChemistryERp99, an abundant, conserved glycoprotein of the endoplasmic reticulum, is homologous to the 90-kDa heat shock protein (hsp90) and the 94-kDa glucose regulated protein (GRP94).
296 Citations1987Richard Mazzarella, M Green
An expressible full-length cDNA clone encoding murine ERp99, an abundant, conserved transmembrane glycoprotein of the endoplasmic reticulum membrane, is isolated and revealed that ER p99 has extensive homology with the 90-kDa heat shock protein of Saccharomyces cerevisiae and the 83-k Da heat shockprotein of Drosophila melanogaster.
Cell ReportsER Stress Causes Rapid Loss of Intestinal Epithelial Stemness through Activation of the Unfolded Protein Response
294 Citations2013Jarom Heijmans, Jooske F. van Lidth de Jeude +16 more
Proceedings of the National Academy of SciencesTransmission of endoplasmic reticulum stress and pro-inflammation from tumor cells to myeloid cells
293 Citations2011Navin R. Mahadevan, Jeffrey J. Rodvold +4 more
It is suggested that transmissible ER stress is a mechanism through which tumor cells can control myeloid cells by directing them toward a proinflammatory phenotype, thus facilitating tumor progression.
Biochimica et Biophysica Acta (BBA) - Molecular Cell ResearchEvolution and function of diverse Hsp90 homologs and cochaperone proteins
284 Citations2011Jill L. Johnson
Diverse HSP90 homologs appear to chaperone different types of client proteins, which may reflect either the pool of clients requiring Hsp90 function or the requirement for cochaperones to target clients to Hsp 90.
Cancer ResearchGRP78 as a Novel Predictor of Responsiveness to Chemotherapy in Breast Cancer
281 Citations2006Eunjung Lee, Peter W. Nichols +4 more
A retrospective cohort study of 127 stage II and III breast cancer patients who were treated with Adriamycin-based chemotherapy suggests an association between GRP78 positivity and shorter TTR and the use of GRp78 as a predictor for chemoresponsiveness and the potential interaction ofGRP78 and/or the UPR pathways with taxanes warrant larger studies.
ElectrophoresisProtein expression profiles in human breast ductal carcinoma and histologically normal tissue
280 Citations1997Luca Bini, Barbara Magi +10 more
The pattern of 32 spots was found to be indicative of epithelial neoplasia and the cancer‐ and tissue‐specificity of the described pattern was assessed by matching to the Swiss‐2DPAGE human liver, hepatoma, lymphoma, erythroleukemia reference maps.
Proceedings of the National Academy of SciencesInhibition of tumor progression by suppression of stress protein GRP78/BiP induction in fibrosarcoma B/C10ME.
279 Citations1996Colin Jamora, Gunther Dennert +1 more
It is reported that molecular inhibition of GRP78/BiP induction in the fibrosarcoma B/C10ME, while not affecting in vitro cell proliferation, causes a dramatic increase in apoptotic cell death upon Ca2+ depletion of the endoplasmic reticulum.
CellInduction of two transformation-sensitive membrane polypeptides in normal fibroblasts by a block in glycoprotein synthesis or glucose deprivation
274 Citations1977Jacques Pouysségur, Robert P. C. Shiu +1 more
The induction of these two proteins by glucose starvation suggests that they have a role in glucose utilization, and two glucose derivatives, glucosamine and 2-deoxyglucose, are known to interfere with the glycosylation process.
Journal of Biological ChemistryInduction of Grp78/BiP by Translational Block
273 Citations2003Shengzhan Luo, Peter Baumeister +3 more
The studies resolve a mechanism responsible for inhibition of Grp78 mRNA induction by ER stress in cells that are functionally null for PERK or devoid of eIF2α phosphorylation and identify the closely related ATF1 and CREB1 as nuclear co-factors that form in vivo complexes with endogenous ATF4.
Journal of Biological ChemistryActivation and Cross-talk between Akt, NF-κB, and Unfolded Protein Response Signaling in 1-LN Prostate Cancer Cells Consequent to Ligation of Cell Surface-associated GRP78
264 Citations2006Uma Kant Misra, Rohit Deedwania +1 more
In conclusion, α2M* promotes cellular proliferation of 1-LN prostate cancer cells by activating MAPK and Akt-dependent signaling, down-regulating apoptotic signaling, and activating unfolded protein response signaling.
Cancer Research(−)−Epigallocatechin Gallate Overcomes Resistance to Etoposide-Induced Cell Death by Targeting the Molecular Chaperone Glucose-Regulated Protein 78
262 Citations2006Svetlana P. Ermakova, Bong Seok Kang +6 more
Results strongly suggested that EGCG could prevent the antiapoptotic effect of GRP78, which usually suppresses the caspase-mediated cell death pathways in drug-treated cancer cells, contributing to the development of drug resistance.
Cell Stress and ChaperonesAn Hsp70 family chaperone, mortalin/mthsp70/PBP74/Grp75: what, when, and where?
259 Citations2002Renu Wadhwa, Kazunari Taira +1 more
Information is compiled and reviewed on the multiple sites and functions of mortalin in different organisms and the relevance of its differential distributions and functions in normal and immortal cell phenotypes is discussed.
Antioxidants and Redox SignalingGRP78: A Multifunctional Receptor on the Cell Surface
258 Citations2009Mario Gonzalez–Gronow, Maria Angelica Selim +2 more
Cell surface GRP78 is found associated with such diverse proteins as the voltage-dependent anion channel (VDAC), the major histocompatibility complex class I (MHC-I), the teratocarcinoma-derived growth factor I (Cripto), and the DnaJ-like protein MTJ-1, which suggests a unique GRP 78 cell surface topography.
CellThe Tumor Suppressor Par-4 Activates an Extrinsic Pathway for Apoptosis
255 Citations2009Ravshan Burikhanov, Yanming Zhao +4 more
Interestingly, extracellular Par-4 induced apoptosis by binding to the stress response protein, glucose-regulated protein-78 (GRP78), expressed at the surface of cancer cells, and activates an extrinsic pathway involving cell surface GRP78 receptor for induction of apoptosis.
PubMedSelective toxicity of MKT-077 to cancer cells is mediated by its binding to the hsp70 family protein mot-2 and reactivation of p53 function.
243 Citations2000Renu Wadhwa, Takumichi Sugihara +6 more
It is reported that MKT-077 binds to an hsp70 family member, mortalin (mot-2), and abrogates its interactions with the tumor suppressor protein, p53, and induced release of wild-type p53 from cytoplasmically sequestered p53-Mot-2 complexes and rescued its transcriptional activation function.
Nucleic Acids ResearchThe mammalian endoplasmic reticulum stress response element consists of an evolutionarily conserved tripartite structure and interacts with a novel stress-inducible complex
239 Citations1999Bappaditya Roy
Cancer ResearchKringle 5 of Human Plasminogen Induces Apoptosis of Endothelial and Tumor Cells through Surface-Expressed Glucose-Regulated Protein 78
236 Citations2005Donald J. Davidson, Catherine J. Haskell +10 more
Recombinant K5 is established as an inhibitor of a stress response pathway, which leads to both endothelial and tumor cell apoptosis, and glucose-regulated protein 78 plays a key role in the antiangiogenic and antitumor activity of K5.
Proceedings of the National Academy of SciencesInduction of glucose-regulated proteins during anaerobic exposure and of heat-shock proteins after reoxygenation.
230 Citations1984J J Sciandra, John R. Subjeck +1 more
The importance of deprivation and release environments in controlling the expression of these two stress protein systems is suggested and it is suggested that their natural expression may be determined by comparable circumstances.
Journal of Cell ScienceEndoplasmic reticulum contains a common, abundant calcium-binding glycoprotein, endoplasmin
230 Citations1986G. Koch, Michael J. Smith +3 more
Calcium-binding studies show that endoplasmin is a major calcium-binding protein in cells, suggesting that at least one of its roles might be in the calcium-storage function of the endoplasmic reticulum.
Journal of Biological ChemistryInactivation of Tumor Suppressor p53 by Mot-2, a hsp70 Family Member
224 Citations1998Renu Wadhwa, Syuichi Takano +6 more
A novel mechanism of p53 inactivation by mot-2 protein is demonstrated, supported by the down-regulation of p 53-responsive genes p21WAF-1 andmdm-2 in mot-1-transfected cells only and an abrogation of nuclear translocation of wild-type p53.
Molecular and Cellular BiologyEndoplasmic Reticulum Stress Induction of the Grp78/BiP Promoter: Activating Mechanisms Mediated by YY1 and Its Interactive Chromatin Modifiers
222 Citations2005Peter Baumeister, Shengzhan Luo +5 more
It is shown that YY1 is an essential coactivator of ATF6 and uncovered their specific interactive domains and a model for the ER stress-mediated transcription factor binding and chromatin modifications at the Grp78 promoter leading to its activation is proposed.
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220 Citations2006Yong Fu, Amy S. Lee
The localization of GRPs on the cell surface of certain cell types suggests that they serve new functions as cell surface receptors for signaling, which could have major clinical implications in the prognosis and treatment of cancer.
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215 Citations2013Pallav D. Patel, Pengrong Yan +10 more
It is shown that Grp94 selectivity is due to the insertion of these compounds into a new allosteric pocket, and new mechanistic evidence explaining why selective Grp 94 inhibition is particularly efficacious in certain breast cancers is provided.
Human PathologyGlucose-regulated protein GRP78 is up-regulated in prostate cancer and correlates with recurrence and survival
209 Citations2007Siamak Daneshmand, Marcus L. Quek +10 more
It is confirmed that GRP78 protein expression is significantly higher in prostate cancer than in benign prostatic tissue and the intensity of expression is significant associated with survival and clinical recurrence.
Journal of Biological ChemistryIdentification of a novel member of mouse hsp70 family. Its association with cellular mortal phenotype.
204 Citations1993Renu Wadhwa, Sunil C. Kaul +2 more
Microinjection of anti-p66 antibody to senescent MEF could transiently stimulate their cell division, which supports the cellular mortality-related function of p66mot-1.
Science Translational MedicineA Blood-Based Proteomic Classifier for the Molecular Characterization of Pulmonary Nodules
197 Citations2013Xiaojun Li, Clive Hayward +21 more
A panel of 13 proteins was discovered that was able to distinguish benign lung nodules from early-stage lung cancers in a clinical study and validated in a second clinical study with new patients, providing insightful information on the disease status of lung nodule beyond the clinical risk factors currently used by physicians.
Journal of Biological ChemistryPurification and Characterization of a Novel Stress Protein, the 150-kDa Oxygen-regulated Protein (ORP150), from Cultured Rat Astrocytes and Its Expression in Ischemic Mouse Brain
196 Citations1996Keisuke Kuwabara, Masayasu Matsumoto +10 more
The data suggest that astroglia respond to oxygen deprivation by redirection of protein synthesis with the appearance of a novel stress protein, ORP150, which may contribute to their adaptive response to ischemic stress, thereby ultimately contributing to enhanced survival of neurons.
Human PathologyOverexpression of GRP78 and GRP94 are markers for aggressive behavior and poor prognosis in gastric carcinomas
189 Citations2008Hua‐chuan Zheng, Hiroyuki Takahashi +5 more
Up-regulated expression of GRP78 and GRP94 was possibly involved in pathogenesis, growth, invasion, and metastasis of gastric carcinomas and were considered objective and effective markers for the aggressive behavior and poor prognosis in gastric cancer.
BiochemistryTargeting Heat Shock Proteins on Cancer Cells: Selection, Characterization, and Cell-Penetrating Properties of a Peptidic GRP78 Ligand
188 Citations2006Young Soo Kim, Antonietta M. Lillo +9 more
The data presented suggest that cyclic peptide Pep42 might be a powerful tool in the construction of drug conjugates designed to selectively kill malignant cancer cells.
The Journal of PathologyMortalin is over‐expressed by colorectal adenocarcinomas and correlates with poor survival
187 Citations2004Sinclair R. Dundas, Laura Lawrie +2 more
It is found that mortalin over‐expression correlates with poor patient survival and, in multivariate analysis, is independent of standard prognostic variables (p = 0.04); and this protein is involved in colorectal neoplasia.
Journal of Biological ChemistryBinding of Activated α2-Macroglobulin to Its Cell Surface Receptor GRP78 in 1-LN Prostate Cancer Cells Regulates PAK-2-dependent Activation of LIMK
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Clinical & Experimental MetastasisAssociation of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer
184 Citations2006Jun Zhang, Yixing Jiang +8 more
It is found that GRP78 was overexpressed in the tumor specimens when compared with the expression in adjacent tumor-free gastric mucosa, and this implies that dysregulated expression ofGRP78 may contribute to the development and progression of gastric cancer.
Circulation ResearchOxidized Low-Density Lipoproteins Trigger Endoplasmic Reticulum Stress in Vascular Cells
184 Citations2008Marie Sanson, Nathalie Augè +9 more
Investigation of whether ER stress is induced by oxLDLs and can be prevented by the ER-associated chaperone ORP150 found it to be prevented, as assessed by the protective effect of specific small interfering RNAs and c-Jun N-terminal kinase inhibitor.
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It is demonstrated that Cripto and GRP78 interact at the cell surfaces of multiple cell lines and that their interaction is independent of prior association within the ER.
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181 Citations2013Ren Liu, Xiu‐Qing Li +14 more
A novel anti-GRP78 monoclonal antibody MAb159 modulates the PI3K pathway and inhibits tumor growth and metastasis and will enter human trials shortly.
OncogeneBlockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways
179 Citations2009Jonathan A. Kelber, Athanasia D. Panopoulos +5 more
It is shown that targeted disruption of the cell surface Cripto/GRP78 complex using shRNAs or GRP78 immunoneutralization precludes Cripti activation of MAPK/PI3K pathways and modulation ofactivin-A, activin-B, Nodal and transforming growth factor-β1 signaling.
Biochemical JournalLocalization of GRP78 to mitochondria under the unfolded protein response
177 Citations2006Fang‐Chun Sun, Shou Wei +4 more
The results indicate that, at least under certain circumstances, the ER-resided chaperone GRP78 can be retargeted to mitochondria and thereby may be involved in correlating UPR signalling between these two organelles.
Diabetes<i>Grp78</i> Heterozygosity Promotes Adaptive Unfolded Protein Response and Attenuates Diet-Induced Obesity and Insulin Resistance
174 Citations2009Risheng Ye, Dae Young Jung +6 more
HFD-induced obesity and type 2 diabetes are improved in Grp78+/− mice, and Adaptive UPR in WAT could contribute to this improvement, linking ER homeostasis to energy balance and glucose metabolism.
PubMedPhotodynamic therapy-mediated oxidative stress can induce expression of heat shock proteins.
173 Citations1996Charles J. Gomer, Stefan W. Ryter +4 more
Results indicate that photosensitizer-generated singlet oxygen exposure can induce in vitro and in vivo HSP-70 expression, and that specific subcellular targets of PDT (which can differ for various sensitizers) are determinants for H SP-70 activation after oxidative stress.
Experimental Cell ResearchHsp70 Family Member, mot-2/mthsp70/GRP75, Binds to the Cytoplasmic Sequestration Domain of the p53 Protein
169 Citations2002Renu Wadhwa
It is demonstrated that perturbation of mot-p53 interactions can be employed to abrogate cytoplasmic retention of wild-type p53 in tumors.
Molecular & Cellular ProteomicsAssociation of Mortalin (HSPA9) with Liver Cancer Metastasis and Prediction for Early Tumor Recurrence
169 Citations2007Xin Yi, John M. Luk +7 more
Mortalin (HSPA9) is associated with HCC metastasis and thus suggested as a tumor marker for predicting early recurrence, which may have immediate clinical applications for cancer surveillance after curative surgery.
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159 Citations2012Seung‐Ah Yoo, Sungyong You +11 more
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PLoS ONERegulation of PERK Signaling and Leukemic Cell Survival by a Novel Cytosolic Isoform of the UPR Regulator GRP78/BiP
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156 Citations2007Sherry Wanderling, Birgitte B. Simen +5 more
Using targeted disruption of the murine GRp94 gene, it is shown that it has essential functions in embryonic development and insulin-like growth factor II is identified as one developmentally important protein whose production depends on the activity of GRP94.
Molecular Cancer ResearchStress Chaperone GRP78/BiP Confers Chemoresistance to Tumor-Associated Endothelial Cells
156 Citations2008Jenilyn J. Virrey, Dezheng Dong +8 more
It is reported that the endoplasmic reticulum chaperone GRP78/BiP is generally highly elevated in the vasculature derived from human glioma specimens, both in situ in tissue and in vitro in primary cell cultures, compared with minimalGRP78 expression in normal brain tissues and blood vessels.
Cell Death and DifferentiationMortalin–p53 interaction in cancer cells is stress dependent and constitutes a selective target for cancer therapy
155 Citations2011W-J Lu, N P Lee +5 more
It is demonstrated that the mortalin–p53 interaction exists in cancer cells that are either physiologically stressed (frequently associated with p53 mutations) or treated with stress-inducing chemicals.
Cancer ResearchTargeted Nanoparticles That Deliver a Sustained, Specific Release of Paclitaxel to Irradiated Tumors
154 Citations2010Ralph J. Passarella, Daniel E. Spratt +8 more
This targeting agent combines a novel recombinant peptide with a paclitaxel-encapsulating nanoparticle that specifically targets irradiated tumors, increasing apoptosis and tumor growth delay in a manner superior to known chemotherapy approaches.
World Journal of GastroenterologyExpression of heat shock proteins (HSP27, HSP60, HSP70, HSP90, GRP78, GRP94) in hepatitis B virus-related hepatocellular carcinomas and dysplastic nodules
151 Citations2005Seung Oe Lim
The expressions of HSPs are commonly up-regulated in HBV-related HCCs and GRP78 might play an important role in the stepwise progression of HBV -related hepatocarcinogenesis, strongly suggesting vascular invasion and intrahepatic metastasis.
HepatologyLiver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice
149 Citations2011Cheng Ji, Neil Kaplowitz +4 more
The findings underscore the importance of GRP78 in managing the physiological client protein load and suppressing apoptosis in hepatocytes, and they support the pathological role of ER stress in the evolution of fatty liver disease under adverse conditions.
PLoS ONECancer Cells Resistant to Therapy Promote Cell Surface Relocalization of GRP78 Which Complexes with PI3K and Enhances PI(3,4,5)P3 Production
148 Citations2013Yi Zhang, Chun-Chih Tseng +4 more
The studies provide a mechanistic explanation for the regulation of the PI3K/AKT signaling by s GRP78 and suggest that targeting sGRP78 may suppress therapeutic resistance in cancer cells and offer a novel strategy to suppressPI3K activity.
Journal of Biological ChemistryBiochemical characterization of the 94- and 78-kilodalton glucose-regulated proteins in hamster fibroblasts.
148 Citations1984Amy S. Lee, Jeffrey R. Bell +1 more
This report concerns further characterization of the 94-kDa and the 78-kDA glucose-regulated proteins which are the major proteins overproduced in hamster fibroblasts when the cells are starved of glucose.
Proceedings of the National Academy of SciencesHuman homologue of murine tumor rejection antigen gp96: 5'-regulatory and coding regions and relationship to stress-induced proteins.
148 Citations1990Robert G. Maki, Lloyd J. Old +1 more
Cancer ResearchA Critical Role for GRP78/BiP in the Tumor Microenvironment for Neovascularization during Tumor Growth and Metastasis
146 Citations2011Dezheng Dong, Christopher J. Stapleton +13 more
In mouse tumor models in which wild-type (WT), syngeneic mammary tumor cells were injected into the host, it was showed that Grp78(+/-) mice suppressed tumor growth and angiogenesis during the early phase but not during the late phase of tumor growth, suggesting that concomitant use of current chemotherapeutic agents and novel therapies against GRP78 may offer a powerful dual approach to arrest cancer initiation, progression, and metastasis.
Biochimica et Biophysica Acta (BBA) - Reviews on CancerGlucose regulated protein 78: A critical link between tumor microenvironment and cancer hallmarks
143 Citations2012Zongwei Li, Zhuoyu Li +2 more
The potential contributions of GRP78 to the acquisition of cancer hallmarks based on intervening in stress responses caused by tumor niche alterations are reviewed.
Cancer Detection and PreventionOverexpression of endoplasmic reticulum molecular chaperone GRP94 and GRP78 in human lung cancer tissues and its significance
142 Citations2005Qi Wang, HE Zhong-zhou +7 more
The overexpression of GRP94 and GRP78 in the cancer tissue correlated with grade of differentiation and stage of tumors, and both were related with the differentiation and progression of the cancer.
Journal of Biological ChemistryThe Role of Grp 78 in α2-Macroglobulin-induced Signal Transduction
141 Citations2002Uma Kant Misra, Mario Gonzalez–Gronow +4 more
It is concluded that Grp 78 is essential for α2M*-induced signal transduction and that a “co-receptor” relationship exists with LRP like that seen with several other ligands and receptors such as the uPA/uPAR system.
Clinical Cancer ResearchExpression of Stress Response Protein Grp78 Is Associated with the Development of Castration-Resistant Prostate Cancer
140 Citations2006Llana Pootrakul, Ram H. Datar +6 more
Findings show that up-regulation of Grp78 is associated with the development of castration resistance, possibly in part by augmenting cell survival as previously suggested, and may serve as an important prognostic indicator of recurrence in a subset of patients with T3N0M0 disease.
Journal of Biological ChemistryThe Endoplasmic Reticulum Chaperone Glycoprotein GRP94 with Ca2+-binding and Antiapoptotic Properties Is a Novel Proteolytic Target of Calpain during Etoposide-induced Apoptosis
137 Citations1999Ramachandra K. Reddy, Jun Lu +1 more
These studies provide new evidence that the cytoprotective GRP94, as in the case of the antiapoptotic protein Bcl-2, can be targets of proteolytic cleavage themselves during the apoptotic process.
OncogeneEndoplasmic reticulum ribosome-binding protein 1 (RRBP1) overexpression is frequently found in lung cancer patients and alleviates intracellular stress-induced apoptosis through the enhancement of GRP78
136 Citations2013H-Y Tsai, Y-F Yang +11 more
RRBP1 is critical for tumor cell survival, which may make it a useful target in lung cancer treatment and a candidate for the development of new targeted therapeutics.
Frontiers in PharmacologyThe Molecular Chaperone GRP78/BiP in the Development of Chemoresistance: Mechanism and Possible Treatment
136 Citations2013Corinna Roller, Danilo Maddalo
Journal of Clinical InvestigationExpression of the endoplasmic reticulum molecular chaperone (ORP150) rescues hippocampal neurons from glutamate toxicity
135 Citations2001Yasuko Kitao, Kentaro Ozawa +10 more
It is shown that an inducible chaperone present in endoplasmic reticulum (ER), the 150-kDa oxygen-regulated protein (ORP150), is expressed both in the human brain after seizure attack and in mouse hippocampus after kainate administration, which underscores a possible role for ER stress in glutamate toxicity and pinpoint a key ER chaper one, ORP150, which contributes to the stress response critical for neuronal survival.
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