Integrity of zinc finger motifs in PML protein is necessary for inducing its degradation by antimony

• Published in: Metallomics 2019-08, Vol.11 (8), p.1419-1429
• Main Authors: Yang, Chang, Hao, Rui, Lan, Yong Fei, Chen, Ye Jia, Wang, Chao, Bu, Na, Wang, Qian Qian, Hussain, Liaqat, Ma, Li Ya, Maimaitiyiming, Yasen, Lu, Xiao Yang, Naranmandura, Hua
• Format: Article
• Language: English
• Subjects: Acute promyeloid leukemia; Antimony; Antimony compounds; Arsenic; Arsenic trioxide; Binding sites; Biodegradation; Cell differentiation; Cell fusion; Cytotoxicity; Degradation; Differentiation (biology); Fusion protein; Integrity; Leukemia; Methylation; Periodic table; PML protein; Pretreatment; Promyeloid leukemia; Proteins; Toxicity; Zinc; Zinc finger proteins
• ISSN: 1756-5901; 1756-591X
• DOI: 10.1039/c9mt00102f

Antimony (Sb) belongs to the same group as arsenic (As) in the periodic table, and both share similar characteristics. However, Sb 2 O 3 (Sb III ) has no methylation capacity, unlike arsenic trioxide (As 2 O 3 ). In the present study, we determined the effect of Sb III on NB4 cells and found that antimony could induce PML-RARα fusion protein degradation, reorganization of PML-NBs, and NB4 cell differentiation with low cytotoxicity. On the other hand, zinc finger motifs in PML protein are considered to be a key target binding site for arsenic-induced PML-RARα protein degradation. Interestingly, antimony and arsenic lost their ability to degrade PML-RARα fusion protein in NB4 cells following pretreatment with phenanthroline ( i.e. , chelator of zinc ions), indicating that the integrity of zinc finger motifs in PML-RARα fusion protein is a fundamental condition for inducing the protein's degradation by antimony and arsenic. Moreover, we found that Sb III could not induce mutant PML ( e.g. , A126V and L218P) solubility change and degradation, similar to As 2 O 3 . In contrast, we found that the organic antimony compound phenylstibine oxide (PSO) could induce mutant PML protein degradation. In conclusion, our results indicate that Sb III might also be a promising agent to treat acute promyelocytic leukemia, in the same manner as As 2 O 3 . The presence of zinc ions in a zinc finger motif of a PML protein is a fundamental requirement for the protein's degradation by antimony.