PML-RARα stabilized by zinc in human acute promyelocytic leukemia NB4 cells

• Published in: Journal of inorganic biochemistry 2017-10, Vol.175, p.92-100
• Main Authors: Zhu, Bo, Wang, Jia-yu, Zhou, Jun-jie, Zhou, Feng, Cheng, Wei, Liu, Ying-ting, Wang, Jie, Chen, Xiao, Chen, Dian-hua, Luo, Lan, Hua, Zi-Chun
• Format: Article
• Language: English
• Subjects: Acute promyelocytic leukemia; Apoptosis; Cell Line, Tumor; Humans; Leukemia, Promyelocytic, Acute - genetics; Leukemia, Promyelocytic, Acute - metabolism; Leukemia, Promyelocytic, Acute - pathology; Nitric oxide; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; PML-RARα degradation; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Proteolysis; Zinc - metabolism; Zinc homeostasis
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2017.07.007

Acute promyelocytic leukemia (APL) is characterized and driven by the promyelocytic leukemia protein-retinoic acid receptor alpha (PML-RARα) fusion gene. Previous studies have highlighted the importance of PML-RARα degradation in the treatment against APL. Considering the presence of two zinc fingers in the PML-RARα fusion protein, we explored the function of zinc homeostasis in maintaining PML-RARα stability. We demonstrated for the first time that zinc depletion by its chelator N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) triggered PML-RARα degradation in NB4 APL cells via the proteasome pathway rather than the autophagy-lysosomal pathway. In contrast, autophagy protected TPEN-mediated PML-RARα degradation in NB4 APL cells. We further demonstrated that crosstalk between zinc homeostasis and nitric oxide pathway played a key role in maintaining PML-RARα stability in NB4 APL cells. These results demonstrate that zinc homeostasis is vital for maintaining PML-RARα stability, and zinc depletion by TPEN may be useful as a potential strategy to trigger PML-RARα degradation in APL cells. We also found that TPEN triggered apoptosis of NB4 APL cells in a time-dependent manner. The relationship between PML-RARα degradation and apoptosis triggered by TPEN deserves further study. Zinc depletion triggers promyelocytic leukemia protein-retinoic acid receptor alpha (PML-RARα) degradation via the proteasome pathway and induces apoptosis in NB4 cells. Autophagy may play a protective role in PML-RARα degradation triggered by zinc depletion. The crosstalk between zinc and nitric oxide pathway is important for PML-RARα stability. [Display omitted] •Zinc stabilized promyelocytic leukemia protein-retinoic acid receptor alpha (PML-RARα).•Zinc depletion triggered PML-RARα degradation via the proteasome pathway.•Autophagy inhibited PML-RARα degradation triggered by zinc depletion.•Crosstalk between zinc and nitric oxide signaling stabilized PML-RARα.•Zinc depletion induced apoptosis in NB4 cells.