Abolition of stress-induced protein synthesis sensitizes leukemia cells to anthracycline-induced death |
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Authors: | Gausdal Gro Gjertsen Bjørn Tore McCormack Emmet Van Damme Petra Hovland Randi Krakstad Camilla Bruserud Øystein Gevaert Kris Vandekerckhove Joël Døskeland Stein Ove |
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Affiliation: | Department of Biomedicine, University of Bergen, Jonas Lies vei 91, Bergen, Norway. |
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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. |
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