title: Molecular chaperone GRP78 enhances aggresome delivery to autophagosomes to promote drug resistance in multiple myeloma.
abstract: Despite the clinical benefit of the proteasome inhibitor bortezomib, multiple myeloma (MM) patients invariably relapse through poorly defined mechanisms. Myeloma cells inevitably develop chemoresistance that leads to disease relapse and patient-related deaths. Studies in tumor cell lines and biopsies obtained from patients refractory to therapy have revealed that myeloma cells adapt to stress by inducing expression of glucose-regulated protein 78 (GRP78), an endoplasmic reticulum (ER) chaperone with anti-apoptotic properties. Treatment of myeloma cells with bortezomib increased GRP78 levels and activated GRP78-dependent autophagy. Expression profiling indicated that GRP78-encoding HSPA5 was significantly upregulated in bortezomib-resistant cells. Co-treatment with the anti-diabetic agent metformin suppressed GRP78 and enhanced the anti-proliferative effect of bortezomib. Bortezomib treatment led to GRP78 co-localization with proteotoxic protein aggregates, known as aggresomes. Pharmacologic suppression, genetic ablation or mutational inactivation of GRP78 followed by bortezomib treatment led to the accumulation of aggresomes but impaired autophagy and enhanced anti-myeloma effect of bortezomib. GRP78 was co-immunoprecipitated with the KDEL receptor, an ER quality control regulator that binds proteins bearing the KDEL motif to mediate their retrieval from the Golgi complex back to the ER. Taken together, we demonstrate that inhibition of GRP78 functional activity disrupts autophagy and enhances the anti-myeloma effect of bortezomib.
authors.affiliation: The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|Division of Hematology and Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt.
authors.forename: Mohamed A Y
authors.initials: MA
authors.lastname: Abdel Malek
authors.affiliation: The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|Division of Hematology and Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Sajjeev
authors.initials: S
authors.lastname: Jagannathan
authors.affiliation: The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|Division of Hematology and Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Malek
authors.affiliation: Department of Clinical Pathology, South Egypt Cancer Institute, Assiut University, Assiut, Egypt.
authors.forename: Douaa M
authors.initials: DM
authors.lastname: Sayed
authors.affiliation: Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt.
authors.forename: Sahar A
authors.initials: SA
authors.lastname: Elgammal
authors.affiliation: Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt.
authors.forename: Hanan G
authors.initials: HG
authors.lastname: Abd El-Azeem
authors.affiliation: Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt.
authors.forename: Nabila M
authors.initials: NM
authors.lastname: Thabet
authors.affiliation: The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|Division of Hematology and Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|University of Cincinnati Cancer Institute, Cincinnati, OH, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Driscoll
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D000069286:Bortezomib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008687:Metformin / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015388:Organelles / Q000187:drug effects* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C064459:KDEL receptor; D061988:Proteasome Inhibitors; D018000:Receptors, Peptide; D000069286:Bortezomib; D008687:Metformin