RXRα ligand Z-10 induces PML-RARα cleavage and APL cell apoptosis through disrupting PML-RARα/RXRα complex in a cAMP-independent manner.
2017
// Lin Xu 1, * , Zhiping Zeng 1, * , Weidong Zhang 1 , Gaoang Ren 1 , Xiaobin Ling 1 , Fengyu Huang 1 , Peizhen Xie 1 , Ying Su 1, 2 , Xiao-kun Zhang 1, 2 , Hu Zhou 1 1 School of
Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China 2 Cancer Center,
Sanford BurnhamPrebys Medical Discovery Institute, La
Jolla, California, USA * These authors have contributed equally to this work Correspondence to: Hu Zhou, email: huzhou@xmu.edu.cn Xiao-kun Zhang, email: xkzhang@xmu.edu.cn 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 translocationt(15;17). All- trans retinoic acid (ATRA) and
arsenic trioxidecure 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 receptorα (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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