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Ectopic expression of Flt3 kinase inhibits proliferation and promotes cell death in different human cancer cell lines

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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.

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Abbreviations

AML:

Acute myeloid leukemia

Flt3ITD:

Flt3 with internal tandem duplication

IL-3:

Interleukin 3

RTK:

Receptor tyrosine kinase

wt:

Wild type

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Acknowledgments

We are grateful to Linn Hodneland, Lena Fjellstad Hansen, Atle Bredhaug, Ann Kristin Frøyset, Lise Fismen, and Hege Avsnes Dale for valuable technical assistance and Ian F. Pryme for proofreading the manuscript. Confocal imaging and electron microscopy were performed at the Molecular Imaging Center (FUGE, Norwegian Research Council), University of Bergen. This work was supported by grants from the Helse Vest Research Fund and The Norwegian Cancer Society (B.T.G.).

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Authors and Affiliations

  1. Proteomics Unit at University of Bergen (PROBE), University of Bergen, Bergen, Norway

    Eystein Oveland

  2. Department of Biomedicine, University of Bergen, Bergen, Norway

    Eystein Oveland & James B. Lorens

  3. Department of Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway

    Line Wergeland & Bjørn Tore Gjertsen

  4. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway

    Randi Hovland

  5. Institute of Medicine, Hematology Section, University of Bergen, Bergen, Norway

    Line Wergeland & Bjørn Tore Gjertsen

  6. Department of Molecular Biology, University of Bergen, Thormøhlensgt. 55, 5020, Bergen, Norway

    Randi Hovland & Kari E. Fladmark

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  1. Eystein Oveland
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  2. Line Wergeland
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  3. Randi Hovland
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  4. James B. Lorens
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  5. Bjørn Tore Gjertsen
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  6. Kari E. Fladmark
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Corresponding author

Correspondence to Kari E. Fladmark.

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Authors Eystein Oveland and Line Wergeland contributed equally to this study and should share the first authorship.

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Oveland, E., Wergeland, L., Hovland, R. et al. Ectopic expression of Flt3 kinase inhibits proliferation and promotes cell death in different human cancer cell lines. Cell Biol Toxicol 28, 201–212 (2012). https://doi.org/10.1007/s10565-012-9216-z

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  • DOI: https://doi.org/10.1007/s10565-012-9216-z

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