RXRα ligand Z-10 induces PML-RARα cleavage and APL cell apoptosis through disrupting PML-RARα/RXRα complex in a cAMP-independent manner.
RXRα ligand Z-10 induces PML-RARα cleavage and APL cell apoptosis through disrupting PML-RARα/RXRα complex in a cAMP-independent manner.
复制标题
RXRα 配体 Z-10 通过以 cAMP 独立的方式破坏 PML-RARα/RXRα 复合物来诱导 PML-RARα 裂解和 APL 细胞凋亡
DOI：
10.18632/oncotarget.14812
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发表时间：
2017-02-14
期刊：
影响因子：
--
通讯作者：
Zhou H
中科院分区：
文献类型：
--
作者：
Xu L;Zeng Z;Zhang W;Ren G;Ling X;Huang F;Xie P;Su Y;Zhang XK;Zhou H
急性早幼粒细胞白血病（APL）的主要致癌驱动因子是源自染色体易位t（15;17）的融合蛋白PML-RARα。全反式维甲酸（ATRA）和三氧化二砷通过直接靶向PML-RARα治疗大多数患者。然而，包括ATRA和砷治疗的耐药在内的主要问题仍然存在于APL的临床治疗中。我们发现化合物Z-10（RXRα的硝基配体）通过诱导caspase介导的PML-RARα降解，强烈促进ATRA敏感和耐药的NB 4细胞的cAMP非依赖性凋亡。RXRα可能通过相互作用对PML-RARα和RARα的稳定性至关重要。Z-10与RXRα的结合显著抑制RXRα与PML-RARα的相互作用，但不抑制RARα的相互作用，导致Z-10选择性诱导PML-RARα降解，但不诱导RARα降解。Z-10的两个衍生物Z-36和Z-38诱导PML-RARα减少和NB 4细胞凋亡的能力增强。因此，RXRα配体Z-10及其衍生物可通过其独特的作用机制同时靶向ATRA敏感和耐药的APL细胞，是治疗APL的潜在药物先导。
The major oncogenic driver of acute promyelocytic leukemia (APL) is the fusion protein PML-RARα originated from the chromosomal translocation t(15;17). All-trans retinoic acid (ATRA) and arsenic trioxide cure most patients by directly targeting PML-RARα. However, major issues including the resistance of ATRA and arsenic therapy still remain in APL clinical management. Here we showed that compound Z-10, a nitro-ligand of retinoid X receptor α (RXRα), strongly promoted the cAMP-independent apoptosis of both ATRA- sensitive and resistant NB4 cells via the induction of caspase-mediated PML-RARα degradation. RXRα was vital for the stability of both PML-RARα and RARα likely through the interactions. The binding of Z-10 to RXRα dramatically inhibited the interaction of RXRα with PML-RARα but not with RARα, leading to Z-10's selective induction of PML-RARα but not RARα degradation. Z-36 and Z-38, two derivatives of Z-10, had improved potency of inducing PML-RARα reduction and NB4 cell apoptosis. Hence, RXRα ligand Z-10 and its derivatives could target both ATRA- sensitive and resistant APL cells through their distinct acting mechanism, and are potential drug leads for APL treatment.