title: The eIF2-alpha kinase HRI is a novel therapeutic target in multiple myeloma.
abstract: Dexamethasone (dex) induces apoptosis in multiple myeloma (MM) cells and is a frontline treatment for this disease. However resistance to dex remains a major challenge and novel treatment approaches are needed. We hypothesized that dex utilizes translational pathways to promote apoptosis in MM and that specific targeting of these pathways could overcome dex-resistance. Global unbiased profiling of mRNA translational profiles in MM cells treated with or without dex revealed that dex significantly repressed eIF2 signaling, an important pathway for regulating ternary complex formation and protein synthesis. We demonstrate that dex induces the phosphorylation of eIF2α resulting in the translational upregulation of ATF4, a known eIF2 regulated mRNA. Pharmacologic induction of eIF2α phosphorylation via activation of the heme-regulated eIF2α kinase (HRI) induced apoptosis in MM cell lines and in primary MM cells from patients with dex-resistant disease. In addition, co-culture with marrow stroma failed to protect MM cells from apoptosis induced by targeting the eIF2 pathway. Combination therapy with rapamycin, an mTOR inhibitor, and BTdCPU, an activator of HRI, demonstrated additive effects on apoptosis in dex-resistant cells. Thus, specific activation of the eIF2α kinase HRI is a novel therapeutic target in MM that can augment current treatment strategies.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA; Department of Medicine, University of Washington Medical Center, 1705 NE Pacific St., Seattle, WA, USA. Electronic address: nburwick@u.washington.edu.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Burwick
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA.
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
authors.forename: Pilar
authors.initials: P
authors.lastname: de la Puente
authors.affiliation: Department of Radiation Oncology, Cancer Biology Division, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
authors.forename: Abdel Kareem
authors.initials: AK
authors.lastname: Azab
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA; Department of Pathology, University of Washington Medical Center, 1705 NE Pacific St., Seattle, WA, USA.
authors.forename: Teresa S
authors.initials: TS
authors.lastname: Hyun
authors.affiliation: Department of Pediatric Hematology/Oncology, Seattle Children's Hospital, 4800 Sand Point Way, Seattle, WA, USA; Department of Pediatrics, University of Washington, 1959 NE Pacific St., Seattle, WA, USA.
authors.forename: Melisa
authors.initials: M
authors.lastname: Ruiz-Gutierrez
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Sanchez-Bonilla
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA.
authors.forename: Tomoka
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Genomics Resource, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Delrow
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA, USA.
authors.forename: Vivian L
authors.initials: VL
authors.lastname: MacKay
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA; Department of Pediatric Hematology/Oncology, Seattle Children's Hospital, 4800 Sand Point Way, Seattle, WA, USA; Department of Pediatrics, University of Washington, 1959 NE Pacific St., Seattle, WA, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamura
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D009101:Multiple Myeloma / Q000188:drug therapy*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D014407:Tumor Cells, Cultured; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*
chemical_list: D003907:Dexamethasone; D019892:eIF-2 Kinase
keywords: Apoptosis; Dexamethasone; Multiple myeloma; eIF2 signaling