title: TRAIL-induced apoptosis of HL60 leukemia cells: two distinct phenotypes of acquired TRAIL resistance that are accompanied with resistance to TNFalpha but not to idarubicin and cytarabine.
abstract: TNF-related apoptosis-inducing ligand (TRAIL) is a proapoptotic cytokine implicated in cancer cell surveillance. A potential of TRAIL as a cancer-specific therapeutic agent has been proposed, either as a single agent or in combination with chemotherapy. Prolonged exposure of TRAIL-sensitive leukemia cell line, wild-type (WT) HL60 cells to recombinant soluble TRAIL or to cytostatic agents, cytarabine and idarubicin, resulted in the establishment of resistant subclones with distinct phenotypic features. The TRAIL resistant HL60 subclones were characterized by decreased expression of TRAIL and TNFalpha death receptors. These resistant subclones had impaired activation of caspases 8 and 10 in response to TRAIL and TNFalpha, decreased TRAIL-induced nuclear translocation of NFkappaB RelA/p65, and dysregulation of the expression of several apoptosis regulators. Among the TRAIL resistant HL60 subclones we identified two separate phenotypes that differed in the expression of CD14, osteoprotegerin, and several apoptosis regulators. Both these TRAIL resistant HL60 subclones were resistant to TNFalpha, suggesting disruption of the extrinsic apoptotic pathway, but not to cytostatic agents, cytarabine and idarubicin. The concurrently derived HL60 subclones were cytarabine and idarubicin-resistant but remained sensitive to TRAIL-induced apoptosis. We identified distinct pathways for the development of HL60 leukemia cell resistance to apoptosis induction. These findings are relevant for the design of more effective strategies for leukemia therapy.
authors.affiliation: Department of Pathophysiology, 1st Medical Faculty, Charles University in Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Klener
authors.forename: Sergiu
authors.initials: S
authors.lastname: Leahomschi
authors.forename: Jan
authors.initials: J
authors.lastname: Molinsky
authors.forename: Tereza
authors.initials: T
authors.lastname: Simonova
authors.forename: Emanuel
authors.initials: E
authors.lastname: Necas
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Gasova
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Cermak
authors.forename: Ludmila
authors.initials: L
authors.lastname: Dolezalova
authors.forename: Ladislav
authors.initials: L
authors.lastname: Andera
authors.forename: Jan
authors.initials: J
authors.lastname: Zivny
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells; D006801:Humans; D015255:Idarubicin / Q000494:pharmacology; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D051017:Apoptosis Regulatory Proteins; D020169:Caspases; D003561:Cytarabine; D015255:Idarubicin; D017346:Protein Serine-Threonine Kinases; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase