Arsenic sulfide promotes apoptosis in retinoid acid resistant human acute promyelocytic leukemic NB4-R1 cells through downregulation of SET protein.
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.
Department of Pathology, General Hospital of Beijing Military Area of PLA, Beijing, China.
Yuwang
Y
Tian
Department of Hematology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Yanfeng
Y
Liu
Department of Hematology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Pengcheng
P
He
Department of Hematology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Feng
F
Liu
Department of Hematology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Naicen
N
Zhou
Department of Hematology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Xiaoyan
X
Cheng
Department of Hematology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Lili
L
Shi
Department of Hematology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Huachao
H
Zhu
Department of Hematology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Jing
J
Zhao
Department of Hematology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Yuan
Y
Wang
Department of Hematology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Mei
M
Zhang
D017209:Apoptosis / Q000187:drug effects*; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D004268:DNA-Binding Proteins; D015536:Down-Regulation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015180:Electrophoresis, Gel, Two-Dimensional; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056488:Histone Chaperones / Q000378:metabolism*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015514:Oncogene Proteins, Fusion; D054648:Protein Phosphatase 2 / Q000378:metabolism; D020543:Proteome / Q000378:metabolism; D040901:Proteomics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology* / Q000627:therapeutic use; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013440:Sulfides / Q000494:pharmacology* / Q000627:therapeutic use*; D014157:Transcription Factors / Q000378:metabolism*
D001152:Arsenicals; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D015514:Oncogene Proteins, Fusion; D020543:Proteome; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012176:Retinoids; C513473:SET protein, human; D013440:Sulfides; D014157:Transcription Factors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C045816:arsenic trisulfide; D054648:Protein Phosphatase 2