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.

Procaspase-3 Overexpression in Cancer: A Paradoxical Observation with Therapeutic Potential

“…PAC-1 has been used as a tool for exploring the effect of direct PC-3 activation in a variety of contexts, highlighted by the recent work of Fuchs and co-workers that elucidated a key role for caspase-3 activity in regulating organ size . PAC-1 has also been utilized for the induction of apoptosis, − for the direct activation of PC-3 downstream of the mitochondria, ,− and has been the subject of detailed preclinical studies. ,− PAC-1 is part of several pharmacological reagent kits (e.g., Sigma LOPAC bioactives library, SCADs inhibitor kit) and has been evaluated in multiple large-scale drug/cell line screens. − The half-life of PAC-1 is ∼25 min in mice and ∼2.1 h in dogs but markedly longer in humans (discussed below), suggesting differences between the rodent and human metabolism of PAC-1.…”

Overview of the structure-based non-genomic effects of the nuclear receptor RXRα

“…It must heterodimerize with its dimeric partner, RXR, to bind DNA and associated coactivators such as p160 family members or PGC-1α [ 63 ]. Xu and Zeng found that the compound Z-10, a nitro-ligand of RXRα [ 64 , 65 ], induces PML-RARα cleavage and APL cell apoptosis by disrupting PML–RARα–RXRα complexes in a cAMP-independent manner. RXRα is vital for the stability of both PML–RARα and RARα, likely through direct interactions.…”

Retinoid X Receptor Alpha Nitro-ligand Z-10 and Its Optimized Derivative Z-36 Reduce β-Amyloid Plaques in Alzheimer’s Disease Mouse Model

“…Z-10 binds to tRXRα and inhibits its activation of TNFα/NFκB signal pathway, thereby leading to TNFα-induced apoptosis in breast cancer cells . In the acute promylocytic leukemia cell line NB4, Z-10 inhibits RXRα/PML-RARα complex formation, resulting in onco-protein PML-RARα degradation and NB4 cell apoptosis . In terms of the variety of RXRα activities, it is conceivable that Z-10 is of other potential RXRα-dependent activities.…”

“…18 In the acute promylocytic leukemia cell line NB4, Z-10 inhibits RXRα/PML-RARα complex formation, resulting in onco-protein PML-RARα degradation and NB4 cell apoptosis. 19 In terms of the variety of RXRα activities, it is conceivable that Z-10 is of other potential RXRα-dependent activities.…”