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

Oncotarget. 2017 Feb 14;8(7):12311-12322. doi: 10.18632/oncotarget.14812.

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.

Keywords: PML-RARα; RXRα; Z-10; cleavage; interaction.

MeSH terms

  • Animals
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / 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
  • Leukemia, Promyelocytic, Acute / metabolism
  • Leukemia, Promyelocytic, Acute / pathology
  • Ligands
  • Naphthalenes / metabolism
  • Naphthalenes / pharmacology*
  • Nitro Compounds / metabolism
  • Nitro Compounds / pharmacology*
  • Oncogene Proteins, Fusion / metabolism*
  • Oxides / pharmacology
  • Protein Binding
  • Proteolysis / drug effects
  • Retinoid X Receptor alpha / metabolism*
  • Styrenes / metabolism
  • Styrenes / pharmacology*
  • Tretinoin / pharmacology

Substances

  • 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