title: Quantitative proteomic analysis to decipher the differential apoptotic response of bortezomib-treated APL cells before and after retinoic acid differentiation reveals involvement of protein toxicity mechanisms.
abstract: The ubiquitin-proteasome system allows the targeted degradation of proteins and plays a critical role in the regulation of many cellular processes. Proteasome inhibition is a recent antitumor therapeutic strategy and bortezomib was the first proteasome inhibitor approved for clinical use. In this study, we used the NB4 cell line to investigate the effects of bortezomib toward acute promyelocytic leukemia cells before and after retinoic acid-induced differentiation. We showed that apoptosis level after bortezomib treatment is higher in NB4 cells than in differentiated NB4 cells. To compare early protein variations upon bortezomib treatment in both NB4 cell populations, we performed a quantitative proteomic analysis based on iTRAQ peptide labeling followed by data analysis with in-house developed scripts. This strategy revealed the regulation of 14 proteins principally involved in protein stress response and apoptosis in NB4 cells after proteasome inhibition. Altogether, our results suggest that the differential level of apoptosis induced by bortezomib treatment in both NB4 cell populations could result from distinct protein toxicity level.
authors.affiliation: CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France. Sandrine.Uttenweiler@ipbs.fr
authors.forename: Sandrine
authors.initials: S
authors.lastname: Uttenweiler-Joseph
authors.forename: David
authors.initials: D
authors.lastname: Bouyssié
authors.forename: David
authors.initials: D
authors.lastname: Calligaris
authors.forename: Pierre G
authors.initials: PG
authors.lastname: Lutz
authors.forename: Bernard
authors.initials: B
authors.lastname: Monsarrat
authors.forename: Odile
authors.initials: O
authors.lastname: Burlet-Schiltz
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D005069:Evaluation Studies as Topic; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000008:administration & dosage; D011506:Proteins / Q000378:metabolism / Q000633:toxicity; D011719:Pyrazines / Q000008:administration & dosage*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects; D014212:Tretinoin / Q000008:administration & dosage*; D025801:Ubiquitin
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D010455:Peptides; D061988:Proteasome Inhibitors; D011506:Proteins; D011719:Pyrazines; D018168:Receptors, Retinoic Acid; D025801:Ubiquitin; D014212:Tretinoin; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex