title: Ligand-induced Flt3-downregulation modulates cell death associated proteins and enhances chemosensitivity to idarubicin in THP-1 acute myeloid leukemia cells.
abstract: Sustained ligand stimulation of the receptor tyrosine kinase Flt3 resulted in its downregulation and a refractory signaling phase in primary acute myeloid leukemia (AML) cells and in the AML cell line THP-1. Stable isotope amino acid labeling in cell culture and mass spectrometry were used to compare protein expression patterns in THP-1 before and after Flt3-downregulation. 375 distinct proteins were identified where ATP-dependent RNA helicase DDX3, HNRPU, Matrin-3, Importin-7 and Bax were among the 25 most upregulated proteins and Hausp/UBP7, UBE2N and ERp29 among the 17 most downregulated. THP-1 cells with receptor downregulation were sensitized to idarubicin-induced apoptosis but not cytarabine. We hypothesize that FL-induced receptor modulation may chemosensitize selected AML subsets.
authors.affiliation: Proteomic Unit at University of Bergen, Bergen, Norway.
authors.forename: Eystein
authors.initials: E
authors.lastname: Oveland
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.forename: Line
authors.initials: L
authors.lastname: Wergeland
authors.forename: Frode
authors.initials: F
authors.lastname: Selheim
authors.forename: Kari E
authors.initials: KE
authors.lastname: Fladmark
authors.forename: Randi
authors.initials: R
authors.lastname: Hovland
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects*; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015255:Idarubicin / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D015398:Signal Transduction; D015854:Up-Regulation; D051941:fms-Like Tyrosine Kinase 3 / Q000187:drug effects* / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D008024:Ligands; D003561:Cytarabine; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D015255:Idarubicin