title: Ectopic expression of Flt3 kinase inhibits proliferation and promotes cell death in different human cancer cell lines.
abstract: Stable ectopic expression of Flt3 receptor tyrosine kinase is usually performed in interleukin 3 (IL-3)-dependent murine cell lines like Ba/F3, resulting in loss of IL-3 dependence. Such high-level Flt3 expression has to date not been reported in human acute myeloid leukemia (AML) cell lines, despite the fact that oncogenic Flt3 aberrancies are frequent in AML patients. We show here that ectopic Flt3 expression in different human cancer cell lines might reduce proliferation and induce apoptotic cell death, involving Bax/Bcl2 modulation. Selective depletion of Flt3-expressing cells occurred in human AML cell lines transduced with retroviral Flt3 constructs, shown here using the HL-60 leukemic cell line. Flt3 expression was investigated in two cellular model systems, the SAOS-2 osteosarcoma cell line and the human embryonic kidney HEK293 cell line, and proliferation was reduced in both systems. HEK293 cells underwent apoptosis upon ectopic Flt3 expression and cell death could be rescued by overexpression of Bcl-2. Furthermore, we observed that the Flt3-induced inhibition of proliferation in HL-60 cells appeared to be Bax-dependent. Our results thus suggest that excessive Flt3 expression has growth-suppressive properties in several human cancer cell lines.
authors.affiliation: Proteomics Unit at University of Bergen-PROBE, University of Bergen, Bergen, Norway.
authors.forename: Eystein
authors.initials: E
authors.lastname: Oveland
authors.forename: Line
authors.initials: L
authors.lastname: Wergeland
authors.forename: Randi
authors.initials: R
authors.lastname: Hovland
authors.forename: James B
authors.initials: JB
authors.lastname: Lorens
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.forename: Kari E
authors.initials: KE
authors.lastname: Fladmark
mesh_terms: D019943:Amino Acid Substitution; D017209:Apoptosis; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D053144:Cell Nucleus Shape; D049109:Cell Proliferation; D002470:Cell Survival; D055785:Gene Knockdown Techniques; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000378:metabolism; D000090243:Nucleophosmin; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C494826:BAX protein, human; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3