Abolition of stress-induced protein synthesis sensitizes leukemia cells to anthracycline-induced death.
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.
Gausdal
Gro
G
Department of Biomedicine, University of Bergen, Jonas Lies vei 91, Bergen, Norway.
Gjertsen
Bjørn Tore
BT
McCormack
Emmet
E
Van Damme
Petra
P
Hovland
Randi
R
Krakstad
Camilla
C
Bruserud
Øystein
Ø
Gevaert
Kris
K
Vandekerckhove
Joël
J
Døskeland
Stein Ove
SO
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
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D009363:Neoplasm Proteins; D010455:Peptides; D003513:Cycloheximide; D003630:Daunorubicin