title: Abolition of stress-induced protein synthesis sensitizes leukemia cells to anthracycline-induced death.
abstract: Anthracycline action has been thought to involve the neosynthesis of proapoptotic gene products and to therefore depend on protein synthesis for optimal effect. We found that inhibition of general, but not rapamycin-sensitive (cap-dependent), protein synthesis in the preapoptotic period enhanced anthracycline-induced acute myelogenous leukemia (AML) cell death, both in vitro and in several animal AML models. Pre-apoptotic anthracycline-exposed AML cells had altered translational specificity, with enhanced synthesis of a subset of proteins, including endoplasmatic reticulum chaperones. The altered translational specificity could be explained by perturbation (protein degradation, truncation, or dephosphorylation) of the cap-dependent translation initiation machinery and of proteins control-ing translation of specific mRNAs. We propose that judiciously timed inhibition of cap-independent translation is considered for combination therapy with anthracyclines in AML.
authors.affiliation: Department of Biomedicine, University of Bergen, Jonas Lies vei 91, Bergen, Norway.
authors.forename: Gro
authors.initials: G
authors.lastname: Gausdal
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.forename: Emmet
authors.initials: E
authors.lastname: McCormack
authors.forename: Petra
authors.initials: P
authors.lastname: Van Damme
authors.forename: Randi
authors.initials: R
authors.lastname: Hovland
authors.forename: Camilla
authors.initials: C
authors.lastname: Krakstad
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Bruserud
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.forename: Joël
authors.initials: J
authors.lastname: Vandekerckhove
authors.forename: Stein Ove
authors.initials: SO
authors.lastname: Døskeland
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D009368:Neoplasm Transplantation; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects*; D051381:Rats; D016019:Survival Analysis
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D009363:Neoplasm Proteins; D010455:Peptides; D003513:Cycloheximide; D003630:Daunorubicin