Oncotarget

Research Papers:

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, Zhiping Zeng, Weidong Zhang, Gaoang Ren, Xiaobin Ling, Fengyu Huang, Peizhen Xie, Ying Su, Xiao-kun Zhang _ and Hu Zhou

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Oncotarget. 2017; 8:12311-12322. https://doi.org/10.18632/oncotarget.14812

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Abstract

Lin Xu1,*, Zhiping Zeng1,*, Weidong Zhang1, Gaoang Ren1, Xiaobin Ling1, Fengyu Huang1, Peizhen Xie1, Ying Su1,2, Xiao-kun Zhang1,2, Hu Zhou1

1School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China

2Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA

*These authors have contributed equally to this work

Correspondence to:

Hu Zhou, email: [email protected]

Xiao-kun Zhang, email: [email protected]

Keywords: Z-10, RXRα, PML-RARα, interaction, cleavage

Received: June 29, 2016     Accepted: December 27, 2016     Published: January 25, 2017

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.


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