title: New insights into the molecular mechanisms underlying sensitivity/resistance to the atypical retinoid ST1926 in acute myeloid leukaemia cells: the role of histone H2A.Z, cAMP-dependent protein kinase A and the proteasome.
abstract: ST1926 is an atypical retinoid and a promising anti-tumour agent with selective apoptotic activity on the leukaemic blast. The anti-tumour activity of the compound has been associated with its capacity to induce DNA double stranded breaks. Target profiling by affinity chromatography coupled to mass spectrometry led to the identification of histone H2A.Z as a protein capable of binding ST1926 specifically. The result was confirmed by studies involving Surface Plasmon Resonance (SPR). This indicates that H2A.Z is a primary target of ST1926 and links the perturbations of the histone pathway observed by microarray analysis to the DNA damage and apoptotic responses caused by the atypical retinoid. Comparison of the whole-genome gene-expression profiles of the ST1926-sensitive NB4 and the ST1926-resistant NB4.437r cell lines demonstrated differential expression of numerous genes. Network analysis of the data indicated enrichment of the cellular pathways controlling cAMP (cyclic adenosine-monophosphate)-dependent signal transduction, proteasome-dependent protein degradation and nuclear histones in NB4.437r cells. Pharmacological inhibition of cAMP-dependent protein kinase A with H89 partially reverted resistance of NB4.437r cells to ST1926. Conversely, inhibition of the proteasome with MG132 or bortezomib blocked the apoptotic response afforded by ST1926 in the NB4 cell line. This last effect was associated with a dramatic reduction in the DNA damage caused by the atypical retinoid. The results corroborate the idea that DNA damage is an important determinant of ST1926 apoptotic activity. More importantly, they demonstrate a proactive role of the proteasome in the DNA damaging and ensuing apoptotic response observed upon the challenge of acute myeloid leukaemia cells with ST1926.
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Fratelli
authors.forename: James Neil
authors.initials: JN
authors.lastname: Fisher
authors.forename: Gabriela
authors.initials: G
authors.lastname: Paroni
authors.forename: Angela Maria
authors.initials: AM
authors.lastname: Di Francesco
authors.forename: Filomena
authors.initials: F
authors.lastname: Pierri
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.forename: Klaus
authors.initials: K
authors.lastname: Godl
authors.forename: Sandra
authors.initials: S
authors.lastname: Marx
authors.forename: Andreas
authors.initials: A
authors.lastname: Tebbe
authors.forename: Claudia
authors.initials: C
authors.lastname: Valli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Gianni
authors.forename: Matteo
authors.initials: M
authors.lastname: Stravalaci
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.forename: Mineko
authors.initials: M
authors.lastname: Terao
authors.forename: Enrico
authors.initials: E
authors.lastname: Garattini
mesh_terms: D000208:Acute Disease; D000218:Adamantane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002934:Cinnamates / Q000378:metabolism / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007976:Leupeptins / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D020349:Surface Plasmon Resonance
chemical_list: C472791:3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid; D002934:Cinnamates; D004791:Enzyme Inhibitors; D006657:Histones; D007546:Isoquinolines; D007976:Leupeptins; D013449:Sulfonamides; C077020:histone H2A.F-Z; D017868:Cyclic AMP-Dependent Protein Kinases; D046988:Proteasome Endopeptidase Complex; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D000218:Adamantane; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde