title: Enhanced Fas-associated death domain recruitment by histone deacetylase inhibitors is critical for the sensitization of chronic lymphocytic leukemia cells to TRAIL-induced apoptosis.
abstract: Chronic lymphocytic leukemia (CLL) is an incurable disease characterized by failure of mature lymphocytes to undergo apoptosis. CLL cells are inherently resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Pretreatment with histone deacetylase inhibitors (HDACi) sensitizes CLL cells to TRAIL-mediated apoptosis primarily via TRAIL-R1 and offers a novel approach for the therapy of CLL and other malignancies. Depsipeptide (romidepsin), a HDACi, did not enhance TRAIL binding to TRAIL-R1, TRAIL-R1 aggregation, or internalization of TRAIL-R1, but it enhanced Fas-associated death domain protein (FADD) recruitment to TRAIL-R1 in the death-inducing signaling complex. Cotreatment with phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, dramatically inhibited the HDACi-mediated increase in FADD recruitment and sensitization to TRAIL-induced apoptosis and both of these were reversed by PKC inhibitors. Thus, enhanced FADD recruitment is a critical step in HDACi-mediated sensitization of CLL cells to TRAIL-induced apoptosis and this step is differentially affected by HDACi and phorbol 12-myristate 13-acetate. Using biotinylated TRAIL and streptactin-tagged TRAIL, we have identified several novel TRAIL receptor interacting proteins, including PKCbeta, lymphocyte-specific protease-1, Lyn, and Syk. These molecules may play an as yet unappreciated role in TRAIL signaling in CLL cells and inhibition of one or more of these kinases/phosphatases may provide a novel target to overcome TRAIL resistance.
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Nick
authors.initials: N
authors.lastname: Harper
authors.forename: Renata
authors.initials: R
authors.lastname: Walewska
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Cohen
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D015153:Blotting, Western; D047630:Depsipeptides / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D051033:Apoptosis Inducing Factor; D047630:Depsipeptides; D053200:Fas-Associated Death Domain Protein; D056572:Histone Deacetylase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D011493:Protein Kinase C; D064546:Protein Kinase C beta; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D006655:Histone Deacetylases; D013755:Tetradecanoylphorbol Acetate