1. Academic Validation
  2. PML-RARα stabilized by zinc in human acute promyelocytic leukemia NB4 cells

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

  • J Inorg Biochem. 2017 Oct;175:92-100. doi: 10.1016/j.jinorgbio.2017.07.007.
Bo Zhu 1 Jia-Yu Wang 1 Jun-Jie Zhou 1 Feng Zhou 1 Wei Cheng 1 Ying-Ting Liu 1 Jie Wang 1 Xiao Chen 1 Dian-Hua Chen 1 Lan Luo 2 Zi-Chun Hua 3
Affiliations

Affiliations

  • 1 The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, PR China.
  • 2 The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, PR China. Electronic address: lanluo@nju.edu.cn.
  • 3 The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, PR China; Changzhou High-Tech Research Institute of Nanjing University, Jiangsu TargetPharma Laboratories Inc., Changzhou, PR China. Electronic address: zchua@nju.edu.cn.
Abstract

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.

Keywords

Acute promyelocytic leukemia; Apoptosis; Nitric oxide; PML-RARα degradation; Zinc homeostasis.

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