title: Pharmacologic screens reveal metformin that suppresses GRP78-dependent autophagy to enhance the anti-myeloma effect of bortezomib.
abstract: Although the therapeutic benefit of proteasome inhibition in multiple myeloma remains unchallenged, drug resistance inevitably emerges through mechanisms that remain elusive. Bortezomib provokes unwanted protein accumulation and the endoplasmic reticulum stress to activate the unfolded protein response (UPR) and autophagy as compensatory mechanisms that restore protein homeostasis. High-throughput screens to detect pharmacologics that modulated autophagy to enhance the anti-myeloma effect of bortezomib revealed metformin, a widely used antidiabetic agent with proven efficacy and limited adverse effects. Metformin co-treatment with bortezomib suppressed induction of the critical UPR effector glucose-regulated protein 78 (GRP78) to impair autophagosome formation and enhance apoptosis. Gene expression profiling of newly diagnosed myeloma patient tumors further correlated the hyperexpression of GRP78-encoding HSPA5 with reduced clinical response to bortezomib. The effect of bortezomib was enhanced with metformin co-treatment using myeloma patient tumor cells and the chemoresistant, stem cell-like side population that may contribute to disease recurrence. The relevance of the findings was confirmed in vivo as shown by metformin co-treatment with bortezomib that delayed the growth of myeloma xenotransplants. Taken together, our results suggest that metformin suppresses GRP78, a key driver of bortezomib-induced autophagy, and support the pharmacologic repositioning of metformin to enhance the anti-myeloma benefit of bortezomib.
authors.affiliation: Division of Hematology and Oncology, 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: S
authors.initials: S
authors.lastname: Jagannathan
authors.affiliation: Division of Hematology and Oncology, 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: M A Y
authors.initials: MA
authors.lastname: Abdel-Malek
authors.affiliation: Division of Hematology and Oncology, 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: E
authors.initials: E
authors.lastname: Malek
authors.affiliation: Division of Hematology and Oncology, 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: N
authors.initials: N
authors.lastname: Vad
authors.affiliation: Division of Hematology and Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|University of Cincinnati Cancer Institute, Cincinnati, OH, USA.
authors.forename: T
authors.initials: T
authors.lastname: Latif
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA, USA.|Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Anderson
authors.affiliation: Division of Hematology and Oncology, 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.|University of Cincinnati Cancer Institute, Cincinnati, OH, USA.|Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Driscoll
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D000069286:Bortezomib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D000069286:Bortezomib; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D008687:Metformin; D019869:Phosphatidylinositol 3-Kinases; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse