Arsenic sulfide promotes apoptosis in retinoid acid resistant human acute promyelocytic leukemic NB4-R1 cells through downregulation of SET protein

Yuwang Tian; Yanfeng Liu; Pengcheng He; Feng Liu; Naicen Zhou; Xiaoyan Cheng; Lili Shi; Huachao Zhu; Jing Zhao; Yuan Wang; Mei Zhang

doi:10.1371/journal.pone.0083184

Arsenic sulfide promotes apoptosis in retinoid acid resistant human acute promyelocytic leukemic NB4-R1 cells through downregulation of SET protein

PLoS One. 2014 Jan 13;9(1):e83184. doi: 10.1371/journal.pone.0083184. eCollection 2014.

Authors

Yuwang Tian¹, Yanfeng Liu², Pengcheng He², Feng Liu², Naicen Zhou², Xiaoyan Cheng², Lili Shi², Huachao Zhu², Jing Zhao², Yuan Wang², Mei Zhang²

Affiliations

¹ Department of Pathology, General Hospital of Beijing Military Area of PLA, Beijing, China.
² Department of Hematology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Abstract

Tetra-arsenic tetra-sulfide (As4S4) is an arsenic compound with anti-tumor activity, especially in acute promyelocytic leukemia (APL) that are resistant to retinoic acid (RA). Although recent studies revealed that the therapeutic action of As4S4 is closely associated with the induction of cellular apoptosis, the exact molecular mechanism of action of As4S4 in RA-resistant APL remains to be clarified. In this study, we found that As4S4-induced apoptosis was accompanied by reduced mRNA and protein expression of SET gene in RA-resistant NB4-R1 cells. Moreover, RNAi knockdown of SET gene further promoted As4S4-induced apoptosis, while SET over-expression inhibited it, suggesting that As4S4 induces apoptosis through the reduction of SET protein in NB4-R1 cells. We also demonstrated that the knockdown of SET gene resulted in the upregulation of protein phosphatase 2 (PP2A) expression and the downregulation of promyelocytic leukemia and retinoic acid receptor α fusion gene (PML-RARα) expression, which were enhanced by As4S4 treatments. By contrast, over-expression of SET gene resulted in PP2A downregulation and PML-RARα upregulation, which were abolished by As4S4 pretreatment. Since PP2A is a pro-apoptotic factor and PMLRARα is an anti-apoptotic factor, our results suggest that As4S4-induced apoptosis in NB4-R1 cells is through the downregulation of SET protein expression, which in turn increases PP2A and reduces PML-RARα expressions to lead to cell apoptosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / drug effects*
Arsenicals / pharmacology*
Arsenicals / therapeutic use*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Shape / drug effects
DNA-Binding Proteins
Down-Regulation / drug effects*
Drug Resistance, Neoplasm / drug effects
Electrophoresis, Gel, Two-Dimensional
Gene Expression Regulation, Neoplastic / drug effects
Gene Knockdown Techniques
Histone Chaperones / metabolism*
Humans
Leukemia, Promyelocytic, Acute / drug therapy*
Leukemia, Promyelocytic, Acute / genetics
Leukemia, Promyelocytic, Acute / pathology
Oncogene Proteins, Fusion
Protein Phosphatase 2 / metabolism
Proteome / metabolism
Proteomics
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA, Small Interfering / metabolism
Retinoids / pharmacology*
Retinoids / therapeutic use
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Sulfides / pharmacology*
Sulfides / therapeutic use*
Transcription Factors / metabolism*

Substances

Arsenicals
DNA-Binding Proteins
Histone Chaperones
Oncogene Proteins, Fusion
Proteome
RNA, Messenger
RNA, Small Interfering
Retinoids
SET protein, human
Sulfides
Transcription Factors
promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
arsenic trisulfide
Protein Phosphatase 2

Grants and funding

This study was supported by the Natural Science Foundation of China (81000218), the Fundamental Research Funds for the Central Universities, the Shaanxi Province Science, and Technology Development Fund, China (nos. 2010K01-135 and 2012KTCL03-12). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.