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Insulin-like growth factor binding protein-3 antagonizes the effects of retinoids in myeloid leukemia cells

Takayuki Ikezoe1, Sakae Tanosaki, Utz Krug

  • 1Division of Hematology/Oncology, Cedars-Sinai Medical Center, Pediatric Endocrinology, University of California at Los Angeles School of Medicine, USA. ikezoet@med.kochi-ms.ac.jp

Blood
|March 18, 2004
PubMed

Insights

Insulin-like growth factor binding protein-3 (IGFBP-3) shows antiproliferative effects in myeloid leukemia cells. It enhances RXR signaling but blunts RAR signaling, impacting retinoid-induced differentiation.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Insulin-like growth factor binding protein-3 (IGFBP-3) exhibits growth suppressive and proapoptotic effects in various cancer types.
  • The role and expression of IGFBP-3 in myeloid leukemia remain largely uncharacterized.

Purpose of the Study:

  • To investigate the expression and functional effects of IGFBP-3 in human myeloid leukemia cell lines.
  • To elucidate the interaction between IGFBP-3, retinoid receptors (RAR and RXR), and their signaling pathways in leukemia.

Main Methods:

  • Analysis of IGFBP-3 expression in myeloid leukemia cell lines.
  • Treatment of leukemia cells with human recombinant IGFBP-3.
  • Signaling assays to assess the impact of IGFBP-3 on RAR, VDR, and RXR mediated signaling.
  • Evaluation of retinoid-induced differentiation in the presence of IGFBP-3.

Main Results:

  • No baseline or ATRA-stimulated IGFBP-3 expression was detected in human myeloid leukemia cell lines.
  • Recombinant IGFBP-3 induced growth arrest and apoptosis in HL-60 and NB4 cells.
  • IGFBP-3 suppressed RAR and VDR signaling while enhancing RXR signaling.
  • IGFBP-3 blunted ATRA-induced differentiation but enhanced RXR-selective ligand-induced differentiation.
  • IGFBP-3 down-regulated retinoid-induced C/EBP epsilon expression transcriptionally.

Conclusions:

  • IGFBP-3 possesses antiproliferative activity against myeloid leukemia cells.
  • IGFBP-3 modulates retinoid signaling by enhancing RXR/RXR pathways and inhibiting RAR/RXR pathways.
  • These findings suggest a complex role for IGFBP-3 in regulating leukemia cell growth and differentiation.

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