Insulin-like growth factor binding protein-3 antagonizes the effects of retinoids in myeloid leukemia cells.
Insulin-like growth factor binding protein-3 (IGFBP-3) can cause growth suppressive and proapoptotic effects on retinoids in many types of cancer cells. However, the expression and effects of IGFBP-3 in myeloid leukemia cells have not been elucidated. In this study, we found no IGFBP-3 expression in the human myeloid leukemia cell lines either at baseline or after stimulation with all-trans retinoic acid (ATRA). Human recombinant IGFBP-3 induced growth arrest and apoptosis of HL-60 and NB4 cells. We have previously identified RXR alpha as a nuclear receptor for IGFBP-3 and have proceeded to examine further the role of this interaction in leukemia cell lines. In signaling assays, IGFBP-3 potently suppressed RAR- and VDR-mediated signaling while enhancing RXR signaling. Interestingly, when IGFBP-3 was administered to these cells in combination with an RAR-selective ligand, the ability of these retinoids to induce differentiation was blunted. On the other hand, IGFBP-3 enhanced the effect of an RXR-selective ligand to induce differentiation of HL-60 and NB4 cells. Further studies showed that IGFBP-3 down-regulated (at the transcriptional level) the retinoid-induced expression of C/EBP epsilon in NB4 cells. Taken together, these results indicate that IGFBP-3 has antiproliferative activity against myeloid leukemia cells; while it enhances signaling through RXR/RXR, it blunts signaling by activated RAR/RXR.
Ikezoe
Takayuki
T
Division 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
Tanosaki
Sakae
S
Krug
Utz
U
Liu
Bingrong
B
Cohen
Pinchas
P
Taguchi
Hirokuni
H
Koeffler
H Phillip
HP
D000077556:Alitretinoin; D017209:Apoptosis / Q000187:drug effects; D002117:Calcitriol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D015870:Gene Expression; D018922:HL-60 Cells; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D018167:Receptors, Calcitriol / Q000187:drug effects / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000187:drug effects / Q000378:metabolism; D047488:Retinoid X Receptors; D012176:Retinoids / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D020298:U937 Cells
C430898:AGN 194204; D005231:Fatty Acids, Unsaturated; D018972:Insulin-Like Growth Factor Binding Protein 3; D011480:Protease Inhibitors; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; D000077556:Alitretinoin; D014212:Tretinoin; D002117:Calcitriol