Research Papers:

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

Qian Qian Wang, Xin Yi Zhou, Yan Fang Zhang, Na Bu, Jin Zhou, Feng Lin Cao and Hua Naranmandura _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2015; 6:25646-25659. https://doi.org/10.18632/oncotarget.4662

Metrics: PDF 1953 views  |   HTML 1992 views  |   ?  


Qian Qian Wang1,2,*, Xin Yi Zhou1,2,*, Yan Fang Zhang1,2, Na Bu2, Jin Zhou3, Feng Lin Cao3, Hua Naranmandura1,2

1Department of Toxicology, School of Medicine and Public Health, Zhejiang University, Hangzhou 310058, China

2College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China

3Department of Hematology and Oncology, The First Clinical College of Harbin Medical University, Harbin 150086, China

*These authors have contributed equally to this work

Correspondence to:

Hua Naranmandura, e-mail: [email protected]

Keywords: acute promyelocytic leukemia, arsenic trioxide, trivalent arsenicals, arsenic binding proteins, monomethylarsonous acid

Received: June 02, 2015     Accepted: July 06, 2015     Published: July 15, 2015


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-RARα 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-RARα fusion protein. Moreover, methylated arsenicals can efficiently lead to cellular apoptosis, however, they are incapable of inducing NB4 cell differentiation.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 4662