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: Lin Xu, Zhiping Zeng, Weidong Zhang, Gaoang Ren, Xiaobin Ling, Fengyu Huang, Peizhen Xie, Ying Su, Xiao-Kun Zhang, Hu Zhou
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 7 Pg. 12311-12322 (Feb 14 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28129653 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Arsenicals
• Ligands
• Naphthalenes
• Nitro Compounds
• Oncogene Proteins, Fusion
• Oxides
• Retinoid X Receptor alpha
• Styrenes
• Z-10 nitro compound
• promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
• beta-nitrostyrene
• Tretinoin
• Cyclic AMP
• Caspases
• Arsenic Trioxide

Topics

• Animals
• Antineoplastic Agents (metabolism, pharmacology)
• Apoptosis (drug effects)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Blotting, Western
• COS Cells
• Caspases (metabolism)
• Cell Line, Tumor
• Chlorocebus aethiops
• Cyclic AMP (metabolism)
• Flow Cytometry
• HEK293 Cells
• Humans
• Leukemia, Promyelocytic, Acute (genetics, metabolism, pathology)
• Ligands
• Naphthalenes (metabolism, pharmacology)
• Nitro Compounds (metabolism, pharmacology)
• Oncogene Proteins, Fusion (metabolism)
• Oxides (pharmacology)
• Protein Binding
• Proteolysis (drug effects)
• Retinoid X Receptor alpha (metabolism)
• Styrenes (metabolism, pharmacology)
• Tretinoin (pharmacology)