title: RXRα ligand Z-10 induces PML-RARα cleavage and APL cell apoptosis through disrupting PML-RARα/RXRα complex in a cAMP-independent manner.
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.
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China.
authors.forename: Gaoang
authors.initials: G
authors.lastname: Ren
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Ling
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China.
authors.forename: Fengyu
authors.initials: F
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China.
authors.forename: Peizhen
authors.initials: P
authors.lastname: Xie
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China.|Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China.|Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Xiao-Kun
authors.initials: XK
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D015153:Blotting, Western; D019556:COS Cells; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D009281:Naphthalenes / Q000378:metabolism / Q000494:pharmacology*; D009574:Nitro Compounds / Q000378:metabolism / Q000494:pharmacology*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology; D011485:Protein Binding; D059748:Proteolysis / Q000187:drug effects; D047490:Retinoid X Receptor alpha / Q000378:metabolism*; D013343:Styrenes / Q000378:metabolism / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D008024:Ligands; D009281:Naphthalenes; D009574:Nitro Compounds; D015514:Oncogene Proteins, Fusion; D010087:Oxides; D047490:Retinoid X Receptor alpha; D013343:Styrenes; C000621791:Z-10 nitro compound; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C011955:beta-nitrostyrene; D014212:Tretinoin; D000242:Cyclic AMP; D020169:Caspases; D000077237:Arsenic Trioxide
keywords: PML-RARα; RXRα; Z-10; cleavage; interaction