Abstract
We present previously unknown evidence that the immunoglobulin heavy chain binding protein BIP/HSPA5, also known as glucose regulated protein (GRP)78, serving as a pivotal component of the pro-survival axis of the unfolded protein response (UPR) signalling network, is abundantly expressed in relapsed B-lineage acute lymphoblastic leukaemia (ALL) and contributes to chemotherapy resistance of leukaemic B-cell precursors. The resistance of B-lineage ALL cells to the standard anti-leukaemic drug vincristine was overcome by the HSPA5 inhibitor epigallocatechin gallate, which inhibits the anti-apoptotic function of HSPA5 by targeting its ATP-binding domain. Notably, chemotherapy-resistant B-lineage ALL cells underwent apoptosis within 48 h of exposure to a doxorubicin-conjugated cell-penetrating cyclic anti-HSPA5 peptide targeting surface-expressed HSPA5 molecules on leukaemia cells. The identification of the HSPA5 as a chemoresistance biomarker and molecular target for B-lineage ALL may lead to new anti-leukaemic treatment strategies that are much needed.
© 2011 Blackwell Publishing Ltd.
MeSH terms
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Adolescent
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / genetics
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Biomarkers, Tumor / antagonists & inhibitors
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / physiology
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Catechin / analogs & derivatives
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Catechin / pharmacology
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Child
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Child, Preschool
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Doxorubicin / pharmacology
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Drug Evaluation, Preclinical / methods
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics
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Endoplasmic Reticulum Chaperone BiP
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Gene Expression Profiling / methods
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Gene Expression Regulation, Neoplastic
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Heat-Shock Proteins / antagonists & inhibitors*
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / physiology
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Humans
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Infant
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Molecular Targeted Therapy / methods
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology*
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Recurrence
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Signal Transduction / genetics
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Tumor Cells, Cultured
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Unfolded Protein Response / genetics
Substances
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Antineoplastic Agents
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Biomarkers, Tumor
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Endoplasmic Reticulum Chaperone BiP
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HSPA5 protein, human
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Heat-Shock Proteins
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Neoplasm Proteins
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Doxorubicin
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Catechin
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epigallocatechin gallate