Arsenic Trioxide Controls the Fate of the PML-RARα Oncoprotein by Directly Binding PML

Abstract

Arsenic, an ancient drug used in traditional Chinese medicine, has attracted worldwide interest because it shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Arsenic trioxide (As2O3) exerts its therapeutic effect by promoting degradation of an oncogenic protein that drives the growth of APL cells, PML-RARalpha (a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor alpha). PML and PML-RARalpha degradation is triggered by their SUMOylation, but the mechanism by which As2O3 induces this posttranslational modification is unclear. Here we show that arsenic binds directly to cysteine residues in zinc fingers located within the RBCC domain of PML-RARalpha and PML. Arsenic binding induces PML oligomerization, which increases its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in enhanced SUMOylation and degradation. The identification of PML as a direct target of As2O3 provides new insights into the drug's mechanism of action and its specificity for APL.

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…As 2 O 3 exerts its powerful therapeutic effect in APL by promoting the degradation of a specific oncogenic protein, the so‐called PML‐RAR α fusion protein (Emadi and Gore 2010; Zhang et al. 2010). In contrast, regarding the other hematologic malignancies, this drug could be effective by activating several pathways leading to cancer cell apoptosis including mitochondrial dysfunction, oxidative stress, and DNA damage (Pelicano et al.…”

“…2007; Zhang et al. 2010). Some studies also suggested that ER stress could be involved in the anticancer action of arsenic trioxide (Du et al.…”

Mutant p53 Protein Is Targeted by Arsenic for Degradation and Plays a Role in Arsenic-mediated Growth Suppression

“…However, arsenic is also a novel promising anticancer agent for treating acute promyelocytic leukemia (APL) 3 and other tumors with mild adverse effects (27)(28)(29)(30). Studies showed that arsenic trioxide produces remissions in patients with APL at least in part through degradation of the aberrant PML-retinoic acid receptor ␣ (PML-RAR␣) fusion protein (32,33). Upon arsenic trioxide exposure, PML undergoes intermolecular disulfide formation and directly binds to arsenic via cysteine residues in zinc fingers located within the RBCC domain of PML and PML-RAR␣.…”

“…Upon arsenic trioxide exposure, PML undergoes intermolecular disulfide formation and directly binds to arsenic via cysteine residues in zinc fingers located within the RBCC domain of PML and PML-RAR␣. Disulfide-linked PML or PML-RAR␣ multimers form nuclear matrix-associated nuclear bodies and become sumoylated and then degraded (32,33). In addition to PML-RAR␣, several other proteins with a high content of cysteine residues and vicinal thiol groups are also targets of arsenic, such as AML1/MDS1/EVI1 protein produced from a fusion gene generated by a t(3;21)(q26;q22) translocation in chronic myelogenous leukemia (34), Gli2 transcriptional effector in the Hedgehog pathway (35), AKT protein (36), BCR/ABL protein produced from a fusion gene generated by a t(9;22) chromosomal translocation in chronic myelogenous leukemia (37), and survivin (38).…”

Sweet fruit from a poisonous kiss

“…In the April 9 th issue of the journal, Science , Zhang et al . provided new and convincing evidence on how AT, an ancient poisonous medicine, plays the tricks on the oncoprotein, PML-RARα, and sheds lights on how a poisonous kiss leads to the sweet fruit [1]. …”