title: Inducing apoptosis in chemotherapy-resistant B-lineage acute lymphoblastic leukaemia cells by targeting HSPA5, a master regulator of the anti-apoptotic unfolded protein response signalling network.
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.
authors.affiliation: Department of Pediatrics, Division of Hematology-Oncology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA. fmuckun@chla.usc.edu
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
authors.forename: Sanjive
authors.initials: S
authors.lastname: Qazi
authors.forename: Zahide
authors.initials: Z
authors.lastname: Ozer
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Garner
authors.forename: Jason
authors.initials: J
authors.lastname: Pitt
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D004317:Doxorubicin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D006801:Humans; D007223:Infant; D058990:Molecular Targeted Therapy / Q000379:methods; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012008:Recurrence; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D009363:Neoplasm Proteins; D004317:Doxorubicin; D002392:Catechin; C045651:epigallocatechin gallate