all-trans-retinoic acid-induced expression and regulation of retinoic acid 4-hydroxylase (CYP26) in human promyelocytic leukemia
all-trans-retinoic acid-induced expression and regulation of retinoic acid 4-hydroxylase (CYP26) in human promyelocytic leukemia
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DOI：
10.1002/ajh.10099
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发表时间：
2002-05-01
影响因子：
12.8
通讯作者：
Lopez-Berestein, G
中科院分区：
文献类型：
--
作者：
Ozpolat, B;Mehta, K;Lopez-Berestein, G
全反式维甲酸（ATRA）可使大多数急性早幼粒细胞白血病（APL）患者完全缓解。然而，由长期每日口服ATRA诱导的ATRA加速代谢已被认为是导致对ATRA治疗的敏感性降低或抗性降低的机制之一。我们研究了CYP 26在早幼粒细胞白血病细胞（NB 4和HL-60）中的表达和调控，CYP 26是一种新型的p450酶，对ATRA具有高度特异性。我们发现，治疗NB 4细胞与药理浓度的ATRA（1 IN）诱导快速和剂量依赖性的CYP 26 mRNA的表达。从培养基中去除ATRA后，两种细胞中的CYP 26表达均恢复至预处理水平。维甲酸受体α（RAR α）特异性拮抗剂（CD 2503）可完全阻断ATRA诱导的HL-60和NB 4细胞CYP 26 mRNA表达。此外，HL-60 R，一个表达非功能性RAR的HL-60亚克隆，由于RAR α配体结合结构域的点突变，未能显示CYP 26 mRNA表达对ATRA的反应。在用RAR α逆转录病毒转导的HL-60 R细胞中，ATRA诱导的CYP 26表达恢复，但在用其他维甲酸受体转导的那些细胞中没有恢复。总之，ATRA诱导CYP 26在髓细胞和早幼粒细胞白血病细胞中的表达，并且这种表达受RAR α调节。ATRA诱导CYP 26表达可能与底物驱动的反馈机制有关，以调节细胞内ATRA的浓度，其在某些克隆中的过度表达可能是导致ATRA治疗敏感性降低或耐药的部分原因。(C)2002 Wiley-Liss，Inc.
all-trans-Retinoic acid (ATRA) induces complete remission in majority of patients with acute promyelocytic leukemia (APL). However, accelerated metabolism of ATRA that is induced by chronic daily administration of oral ATRA has been implicated as one of the mechanisms leading to a reduced sensitivity or resistance to ATRA therapy. We investigated the expression and regulation of CYP26, a novel p450 enzyme, which is highly specific for ATRA, in promyelocytic leukemia cells (NB4 and HL-60). We found that treatment of NB4 cells with a pharmacological concentration of ATRA (1 IN) induced rapid and dose-dependent expression of CYP26 mRNA. The CYP26 expression returned to pretreatment levels in both cells after ATRA was removed from the media. Retinoic acid receptor-alpha (RARalpha) specific antagonist (CD2503) totally abolished the ATRA-induced expression of CYP26 mRNA in HL-60 and NB4 cells. Furthermore, HL-60R, a HL-60 subclone expressing nonfunctional RAR because of a point mutation in the ligand-binding domain of RARalpha, failed to show CYP26 mRNA expression in response to ATRA. ATRA-induced expression of CYP26 was restored in HL-60R cells retrovirally transduced with RARa, but not in those cells transduced with the other retinoid receptors. In conclusion, ATRA induces expression of CYP26 in myeloid and promyelocytic leukemia cells and this expression is modulated by RARa. The induction of CYP26 expression by ATRA treatment might be related to a substrate-driven feedback mechanism to regulate intracellular concentrations of ATRA and its over expression in some clones may be partly responsible for reduced sensitivity or resistance to ATRA therapy. (C) 2002 Wiley-Liss, Inc.