Ikezoe Takayuki, Tanosaki Sakae, Krug Utz, Liu Bingrong, Cohen Pinchas, Taguchi Hirokuni, Koeffler H Phillip
Division of Hematology/Oncology, Cedars-Sinai Medical Center, Pediatric Endocrinology, University of California at Los Angeles School of Medicine, USA.
Blood. 2004 Jul 1;104(1):237-42. doi: 10.1182/blood-2003-07-2203. Epub 2004 Mar 16.
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.
胰岛素样生长因子结合蛋白-3（IGFBP-3）可在多种癌细胞中对类视黄醇产生生长抑制和促凋亡作用。然而，IGFBP-3在髓系白血病细胞中的表达及作用尚未阐明。在本研究中，我们发现人髓系白血病细胞系在基线状态或经全反式维甲酸（ATRA）刺激后均无IGFBP-3表达。人重组IGFBP-3可诱导HL-60和NB4细胞生长停滞及凋亡。我们之前已鉴定出RXRα是IGFBP-3的核受体，并进一步研究了这种相互作用在白血病细胞系中的作用。在信号转导分析中，IGFBP-3可有效抑制RAR和VDR介导的信号转导，同时增强RXR信号转导。有趣的是，当将IGFBP-3与RAR选择性配体联合应用于这些细胞时，这些类视黄醇诱导分化的能力减弱。另一方面，IGFBP-3增强了RXR选择性配体诱导HL-60和NB4细胞分化的作用。进一步研究表明，IGFBP-3（在转录水平）下调了NB4细胞中类视黄醇诱导的C/EBPε表达。综上所述，这些结果表明IGFBP-3对髓系白血病细胞具有抗增殖活性；虽然它增强了通过RXR/RXR的信号转导，但减弱了活化的RAR/RXR的信号转导。
