RXR? ligand Z-10 induces PML-RAR? cleavage and APL cell apoptosis through disrupting PML-RAR?/RXR? complex in a cAMP-independent manner.

ABSTRACT: The major oncogenic driver of acute promyelocytic leukemia (APL) is the fusion protein PML-RAR? originated from the chromosomal translocation t(15;17). All-trans retinoic acid (ATRA) and arsenic trioxide cure most patients by directly targeting PML-RAR?. 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 ? (RXR?), strongly promoted the cAMP-independent apoptosis of both ATRA- sensitive and resistant NB4 cells via the induction of caspase-mediated PML-RAR? degradation. RXR? was vital for the stability of both PML-RAR? and RAR? likely through the interactions. The binding of Z-10 to RXR? dramatically inhibited the interaction of RXR? with PML-RAR? but not with RAR?, leading to Z-10's selective induction of PML-RAR? but not RAR? degradation. Z-36 and Z-38, two derivatives of Z-10, had improved potency of inducing PML-RAR? reduction and NB4 cell apoptosis. Hence, RXR? 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.

SUBMITTER: Xu L 

PROVIDER: S-EPMC5355346 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature