Arsenic Trioxide Activate Transcription of Heme Oxygenase-1 by Promoting Nuclear Translocation of NFE2L2.
In a previous study, we found that induced expression of Heme Oxygenase-1 (HO-1) is responsible for the resistance of human osteosarcoma MG63 cells to the chemotherapeutic agent arsenic trioxide (ATO). The present study was aimed at investigating the molecular mechanisms underlying the induction of HO-1 that occurs after exposure of MG63 cells to ATO. First, using RT-QPCT and Western-blot, we found that ATO strongly induced the expression of heme oxygenase-1 (HO-1) in these human osteosarcoma cells. Then by analyzing HO-1 mRNA of MG63 cells exposed to ATO in the presence and absence of a transcription inhibitor Actinomycin-D (Act-D), we demonstrated that ATO activates HO-1 expression in MG63 cells by regulating the transcription of the gene. Finally, through the analysis of the NFE2L2 protein levels among the total cellular and nuclear proteins by Western-blot and Immunocytochemical staning, we determined that ATO enhanced the nuclear translocation of nuclear factor erythroid 2-like 2 (NFE2L2), also known as Nrf2. From these results we have concluded that transcription activation of HO-1 resulting from the nuclear translocation of NFE2L2 is the underlying molecular mechanism for its high induction, which, in turn, is responsible for the resistance of human osteosarcoma cells to ATO treatment.
1. Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China.
Zhen
Z
Yue
1. Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China ; 3. Current address: Institute of Basic Medical Sciences, College of Life Science, Chinese PLA General Hospital, Beijing 100853, China.
Lingzhi
L
Zhong
1. Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China ; 2. The Second Hospital of Jilin University, Changchun, P.R. China.
Yan
Y
Mou
1. Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China.
Xiaotong
X
Wang
1. Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China.
Haiying
H
Zhang
1. Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China.
Yang
Y
Wang
2. The Second Hospital of Jilin University, Changchun, P.R. China.
Jianxin
J
Xia
1. Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China.
Ronggui
R
Li
2. The Second Hospital of Jilin University, Changchun, P.R. China.
Zonggui
Z
Wang
D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D012516:Osteosarcoma / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D014158:Transcription, Genetic
D000970:Antineoplastic Agents; D001152:Arsenicals; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010087:Oxides; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D000077237:Arsenic Trioxide
Arsenic trioxide; Nuclear Translocation; heme oxygenase-1; nuclear factor erythroid 2-like 2; osteosarcoma