Methylated arsenic metabolites bind to PML protein but do not induce cellular differentiation and PML-RARα protein degradation.

Content Provider	Europe PMC
Author	Wang, Qian Qian Zhou, Xin Yi Zhang, Yan Fang Bu, Na Zhou, Jin Cao, Feng Lin Naranmandura, Hua
Copyright Year	2015
Abstract	Arsenic trioxide (As2O3) is one of the most effective therapeutic agents used for patients with acute promyelocytic leukemia (APL). The probable explanation for As2O3-induced cell differentiation is the direct targeting of PML-RARα oncoprotein by As2O3, which results in initiation of PML-RARa degradation. However, after injection, As2O3 is rapidly methylated in body to different intermediate metabolites such as trivalent monomethylarsonous acid (MMAIII) and dimethylarsinous acid (DMAIII), therefore, it remains unknown that which arsenic specie is actually responsible for the therapeutic effects against APL. Here we have shown the role of As2O3 (as iAsIII) and its intermediate metabolites (i.e., MMAIII/DMAIII) in NB4 cells. Inorganic iAsIII predominantly showed induction of cell differentiation, while MMAIII and DMAIII specifically showed to induce mitochondria and endoplasmic reticulum-mediated apoptosis, respectively. On the other hand, in contrast to iAsIII, MMAIII showed stronger binding affinity for ring domain of PML recombinant protein, however, could not induce PML protein SUMOylation and ubiquitin/proteasome degradation. In summary, our results suggest that the binding of arsenicals to the ring domain of PML proteins is not associated with the degradation of PML-RARa fusion protein. Moreover, methylated arsenicals can efficiently lead to cellular apoptosis, however, they are incapable of inducing NB4 cell differentiation.
Journal	Oncotarget
Volume Number	6
PubMed Central reference number	PMC4694856
Issue Number	28
PubMed reference number	26213848
e-ISSN	19492553
DOI	10.18632/oncotarget.4662
Language	English
Publisher	Impact Journals LLC
Publisher Date	2015-09-01
Access Restriction	Open
Rights License	This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: © 2015 Wang et al.
Subject Keyword	acute promyelocytic leukemia arsenic trioxide trivalent arsenicals arsenic binding proteins monomethylarsonous acid
Content Type	Text
Resource Type	Article
Subject	Oncology