Abolition of stress-induced protein synthesis sensitizes leukemia cells to anthracycline-induced death
2008; Elsevier BV; Volume: 111; Issue: 5 Linguagem: Inglês
10.1182/blood-2007-07-103242
ISSN1528-0020
AutoresGro Gausdal, Bjørn Tore Gjertsen, Emmet McCormack, Petra Van Damme, Randi Hovland, Camilla Krakstad, Øystein Bruserud, Kris Gevaert, Joël Vandekerckhove, Stein Ove Døskeland,
Tópico(s)RNA Interference and Gene Delivery
ResumoAnthracycline 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.
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