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The suppressive effect of arsenic trioxide on TET2-FOXP3-Lyn-Akt axis-modulated MCL1 expression induces apoptosis in human leukemia cells.
- Source :
-
Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2018 Nov 01; Vol. 358, pp. 43-55. Date of Electronic Publication: 2018 Sep 10. - Publication Year :
- 2018
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Abstract
- Arsenic trioxide (ATO) has been reported to inhibit the activity of Ten-eleven translocation methylcytosine dioxygenase (TET). TET modulates FOXP3 expression, while dysregulation of FOXP3 expression promotes the malignant progression of leukemia cells. We examined the role of TET-FOXP3 axis in the cytotoxic effects of ATO on the human acute myeloid leukemia cell line, U937. ATO-induced apoptosis in U937 cells was characterized by activation of caspase-3/-9, mitochondrial depolarization, and MCL1 downregulation. In addition, ATO-treated U937 cells showed ROS-mediated inhibition of TET2 transcription, leading to downregulation of FOXP3 expression and in turn, suppression of FOXP3-mediated activation of Lyn and Akt. Overexpression of FOXP3 or Lyn minimized the suppressive effect of ATO on Akt activation and MCL1 expression. Promoter luciferase activity and chromatin immunoprecipitation assays revealed the crucial role of Akt-mediated CREB phosphorylation in MCL1 transcription. Further, ATO-induced Akt inactivation promoted GSK3β-mediated degradation of MCL1. Transfection of constitutively active Akt expression abrogated ATO-induced MCL1 downregulation. MCL1 overexpression lessened the ATO-induced depolarization of mitochondrial membrane and increased the viability of ATO-treated cells. Thus, our data suggest that ATO induces mitochondria-mediated apoptosis in U937 cells through its suppressive effect on TET2-FOXP3-Lyn-Akt axis-modulated MCL1 transcription and protein stabilization. Our findings also indicate that the same pathway underlies ATO-induced death in human leukemia HL-60 cells.<br /> (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Subjects :
- Antineoplastic Agents therapeutic use
Antineoplastic Agents toxicity
Apoptosis drug effects
Apoptosis physiology
Arsenic Trioxide therapeutic use
DNA-Binding Proteins biosynthesis
Dioxygenases
Dose-Response Relationship, Drug
Forkhead Transcription Factors biosynthesis
Gene Expression Regulation, Neoplastic
HL-60 Cells
Humans
Leukemia drug therapy
Myeloid Cell Leukemia Sequence 1 Protein biosynthesis
Myeloid Cell Leukemia Sequence 1 Protein genetics
Proto-Oncogene Proteins biosynthesis
Proto-Oncogene Proteins c-akt metabolism
U937 Cells
src-Family Kinases biosynthesis
Arsenic Trioxide toxicity
DNA-Binding Proteins antagonists & inhibitors
Forkhead Transcription Factors antagonists & inhibitors
Leukemia metabolism
Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors
Proto-Oncogene Proteins antagonists & inhibitors
Proto-Oncogene Proteins c-akt antagonists & inhibitors
src-Family Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0333
- Volume :
- 358
- Database :
- MEDLINE
- Journal :
- Toxicology and applied pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 30213730
- Full Text :
- https://doi.org/10.1016/j.taap.2018.09.008