RXRα ligand Z-10 induces PML-RARα cleavage and APL cell apoptosis through disrupting PML-RARα/RXRα complex in a cAMP-independent manner.

Lin Xu,Fengyu Huang,Peizhen Xie,Weidong Zhang,Hu Zhou,Xiaobin Ling,Xiao-Kun Zhang,Gaoang Ren,Ying Su,Zhiping Zeng

doi:10.18632/oncotarget.14812

Lin Xu, Fengyu Huang + Show 8 more

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https://doi.org/10.18632/oncotarget.14812

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Abstract

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.

Highlights

Acute promyelocytic leukemia (APL) originates from the specific chromosomal translocations mostly between chromosomes 15 and 17, leading to the occurrence of the fused oncogene promyelocytic leukemia - retinoic acid receptor-α (PML-RARα) [1]
We report that Z-10 induced PMLRARα degradation and the apoptosis of both ATRAsensitive and resistant acute promyelocytic leukemia (APL) cells in a cAMP-independent manner
Both Z-10 and arsenic at 1 μM significantly promoted NB4 cell apoptosis comparing with All-trans retinoic acid (ATRA) (8.07%, 7.38% and 4.76% NB4 cells underwent apoptosis in the presence of Z-10, arsenic, and ATRA, respectively) (Figure 1C)

Summary

Introduction

Acute promyelocytic leukemia (APL) originates from the specific chromosomal translocations mostly between chromosomes 15 and 17, leading to the occurrence of the fused oncogene promyelocytic leukemia - retinoic acid receptor-α (PML-RARα) [1]. PML is the organizer of a nuclear structure known as the PML nuclear bodies (NBs), which is important for maintaining cellular homeostasis [5, 6]. Another pathogenic activity of PML-RARα is to disrupt the PML nuclear bodies through its interaction with PML [7]. All-trans-retinoic acid (ATRA) induces the transcriptional activity of PML-RARα, leading to the induction of RARα-targeted genes and the differentiation of promyelocyte [2]. Arsenic trioxide binds to the PML moiety, leading to SUMO-dependent and ubiquitin-mediated degradation of PML-RARα [15, 16]. Because arsenic targets to the PML moiety, it can overcome ATRA-resistance in some cases [13]

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