Methylated arsenic metabolites bind to PML protein but do not induce cellular differentiation and PML-RARα protein degradation.
Methylated arsenic metabolites bind to PML protein but do not induce cellular differentiation and PML-RARα protein degradation.
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甲基化砷代谢物与 PML 蛋白结合，但不诱导细胞分化和 PML-RARα 蛋白降解
DOI：
10.18632/oncotarget.4662
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发表时间：
2015-09-22
期刊：
影响因子：
--
通讯作者：
Naranmandura H
中科院分区：
文献类型：
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作者：
Wang QQ;Zhou XY;Zhang YF;Bu N;Zhou J;Cao FL;Naranmandura H
三氧化二砷（As 2 O3）是治疗急性早幼粒细胞白血病（APL）的最有效药物之一。As_2O_3诱导细胞分化的可能原因是As_2O_3直接靶向PML-RARα癌蛋白，导致PML-RAR α降解。然而，注射后，As 2 O3在体内迅速甲基化为不同的中间代谢产物，如三价单甲基亚胂酸（MMAIII）和二甲基亚胂酸（DMAIII），因此，仍然不知道哪种砷物种实际上负责抗APL的治疗作用。在这里，我们已经显示了As 2 O3（作为iAsIII）及其中间代谢物（即，MMAIII/DMAIII）。无机iAsIII主要表现为诱导细胞分化，而MMAIII和DMAIII分别特异性地表现为诱导线粒体和内质网介导的凋亡。另一方面，与iAsIII相比，MMAIII对PML重组蛋白的环结构域表现出更强的结合亲和力，但不能诱导PML蛋白SUMO化和泛素/蛋白酶体降解。总之，我们的研究结果表明砷与PML蛋白的环结构域的结合与PML-RAR α融合蛋白的降解无关。此外，甲基化砷可以有效地导致细胞凋亡，但不能诱导NB 4细胞分化。
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.