Combined RARα- and RXR-specific ligands overcome N-myc-associated retinoid resistance in neuroblastoma cells
Combined RARα- and RXR-specific ligands overcome N-myc-associated retinoid resistance in neuroblastoma cells
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DOI：
10.1016/s0006-291x(03)00177-3
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发表时间：
2003-03-14
影响因子：
3.1
通讯作者：
Marshall, GM
中科院分区：
文献类型：
--
作者：
Nguyen, T;Hocker, JE;Marshall, GM
维甲酸通过与核维甲酸受体蛋白相互作用诱导人神经母细胞瘤细胞在体外经历生长抑制和神经炎分化。在这项研究中，我们发现，三种不同的神经母细胞瘤细胞系表现出广泛的变化，其反应的生长抑制作用的视黄酸受体（RAR）激动剂，全反式视黄酸（aRA）。对aRA生长抑制作用的抗性与N-myc基因扩增的存在相关，而不是aRA诱导的RAR β水平。在没有内源性N-myc表达的神经母细胞瘤细胞系中，N-myc的过度表达导致类维生素A诱导的生长抑制显著减少。RXR和RAR α的受体特异性类维生素A激动剂的组合显著增强了N-myc扩增的神经母细胞瘤细胞对aRA生长抑制作用的敏感性。我们的研究结果表明，联合受体特异性类维生素A治疗可以克服N-myc介导的类维生素A耐药性，可能是一种更有效的化学预防策略。(C)2003 Elsevier Science（美国）。All rights reserved.
Retinoids induce human neuroblastoma cells to undergo growth inhibition and neuritic differentiation in vitro, through interactions with nuclear retinoid receptor proteins. In this study, we found that three different neuroblastoma cell lines exhibited wide variation in their responsiveness to the growth inhibitory effects of the retinoic acid receptor (RAR) agonist, all-trans-retinoic acid (aRA). Resistance to the growth inhibitory effect of aRA correlated with the presence of N-myc gene amplification and not aRA-induced RARbeta levels. Over-expression of N-myc in a neuroblastoma cell line with no endogenous N-myc expression caused a marked reduction in retinoid-induced growth inhibition. Combination of receptor-specific retinoid agonists for RXR and RARalpha significantly enhanced the sensitivity of N-myc-amplified neuroblastoma cells to the growth inhibitory effects of aRA. Our results indicate that combination receptor-specific retinoid therapy can overcome N-myc-mediated retinoid resistance and may be a more effective chemo-preventive strategy in the disease. (C) 2003 Elsevier Science (USA). All rights reserved.