title: Multi-level disruption of the extrinsic apoptotic pathway mediates resistance of leukemia cells to TNF-related apoptosis-inducing ligand (TRAIL).
abstract: Disruption of apoptotic pathways belongs to commonly reported molecular mechanisms that underlie cancer drug resistance. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL, Apo2L) is a cytokine of the TNF family with selective anti-tumor activity and minimal toxicity toward healthy tissues. Primary leukemia cells are, however, largely intrinsically resistant to TRAIL-induced apoptosis. In this study we analyzed molecular differences between TRAIL-resistant K562 cell line and TRAIL-sensitive K562 clones. We demonstrate that TRAIL-sensitive K562 cells differ from the TRAIL-resistant cell line by cell surface downregulation of TRAIL decoy receptor 1, upregulation of both TRAIL death receptors, enhanced assembly and improved functioning of the death-inducing signaling complex, and increased cytoplasmic protein expression of CASP8 and key proapoptotic BCL2 members BID, BIM, BAD and BAK. The molecular basis of the intrinsic leukemia cell TRAIL resistance thus appears a consequence of the multi-level disruption of the extrinsic apoptotic pathway. The results of this study also suggest that the leukemia TRAIL-resistance is functional, leaving a possibility of overcoming the resistance by preexposure of the leukemia cells to potent TRAIL sensitizers, e.g. BH3-mimetics.
authors.affiliation: Charles University, Prague, Czech Republic.
authors.forename: S
authors.initials: S
authors.lastname: Leahomschi
authors.forename: J
authors.initials: J
authors.lastname: Molinsky
authors.forename: M
authors.initials: M
authors.lastname: Klanova
authors.forename: L
authors.initials: L
authors.lastname: Andera
authors.forename: M
authors.initials: M
authors.lastname: Peterka
authors.forename: Z
authors.initials: Z
authors.lastname: Gasova
authors.forename: P
authors.initials: P
authors.lastname: Klener
authors.forename: M
authors.initials: M
authors.lastname: Trneny
authors.forename: E
authors.initials: E
authors.lastname: Necas
authors.forename: T
authors.initials: T
authors.lastname: Simonova
authors.forename: J
authors.initials: J
authors.lastname: Zivny
authors.forename: P
authors.initials: P
authors.lastname: Klener
mesh_terms: D017209:Apoptosis; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020014:K562 Cells; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000032:analysis; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha