Submitted July 25, 2007
Accepted December 16, 2007
Abolition of stress-induced protein synthesis sensitizes leukemia cells to anthracycline-induced death
Gro Gausdal, Bjorn Tore Gjertsen, Emmet McCormack, Petra Van Damme, Randi Hovland, Camilla Krakstad, Oystein Bruserud, Kris Gevaert, Joel Vandekerckhove, and Stein Ove Doskeland*
Department of Biomedicine, University of Bergen, Bergen, Norway
Institute of Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway
Department of Medical Protein Research, Ghent University, Ghent, Belgium
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
Department of Biochemistry, University of Ghent, Ghent, Norway
* Corresponding author; email: stein.doskeland{at}biomed.uib.no.
Anthracycline action has been thought to involve the neosynthesis of pro-apoptotic gene products, and therefore depend on protein synthesis for optimal effect. We found that inhibition of general, but not rapamycin-sensitive (cap-dependent), protein synthesis in the pre-apoptotic period enhanced anthracycline-induced 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 ER 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 controlling translation of specific mRNAs. We propose that judiciously timed inhibition of cap-independent translation is considered for combination therapy with anthracyclines in AML.
