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Ligand activation of peroxisome proliferator-activated receptor gamma induces apoptosis of leukemia cells by down-regulating the c-myc gene expression via blockade of the Tcf-4 activity.
- Source :
-
Cell death and differentiation [Cell Death Differ] 2002 May; Vol. 9 (5), pp. 513-26. - Publication Year :
- 2002
-
Abstract
- The peroxisome proliferator-activated receptor gamma (PPAR gamma), a member of the nuclear receptor superfamily, is expressed at highest levels in adipose tissue and functions as a central regulator in the process of adipocyte differentiation. In the present study, we showed that human leukemic cell lines, not only myeloid but also lymphoid, express PPAR gamma and its activation by natural ligand (15-deoxy-Delta(12,14) - prostaglandin J(2)) and synthetic ligand (troglitazone) profoundly inhibited their proliferation by induction of apoptosis preferentially in the serum-free culture. We pursued its mechanism using the representative cell lines, and found that induction of apoptosis was accompanied by caspase-3 activation and specifically blocked by its inhibitor. While status of several apoptosis-related molecules remained unchanged, the c-Myc expression was markedly down-regulated within 24 h after troglitazone treatment. The c-myc mRNA levels were dramatically reduced at 1 h and became undetectable at 12 h after troglitazone treatment, which proved to be accompanied by complete blockade of the Tcf-4 activity in the electrophoretic mobility shift assay. We succeeded in establishing HL-60 cell lines growing well in the presence of troglitazone in the long-term serum-free culture. They showed neither induction of apoptosis nor down-regulation of the c-Myc expression via blockade of the Tcf-4 activity after troglitazone treatment. This is the first identification of the linkage between PPAR gamma-mediated apoptosis and down-regulation of the c-myc gene expression.
- Subjects :
- Antineoplastic Agents pharmacology
Caspase 3
Chromans pharmacology
DNA-Binding Proteins metabolism
Down-Regulation
Drug Resistance, Neoplasm physiology
Enzyme Activation drug effects
Gene Expression physiology
HL-60 Cells
Humans
NF-kappa B metabolism
Nucleic Acid Synthesis Inhibitors pharmacology
Proto-Oncogene Proteins c-myc genetics
RNA, Messenger biosynthesis
Receptors, Cytoplasmic and Nuclear physiology
TCF Transcription Factors
Thiazoles pharmacology
Transcription Factor 7-Like 2 Protein
Transcription Factors physiology
Troglitazone
Tumor Cells, Cultured
Apoptosis physiology
Caspases metabolism
Proto-Oncogene Proteins c-myc biosynthesis
Receptors, Cytoplasmic and Nuclear metabolism
Thiazolidinediones
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1350-9047
- Volume :
- 9
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cell death and differentiation
- Publication Type :
- Academic Journal
- Accession number :
- 11973610
- Full Text :
- https://doi.org/10.1038/sj.cdd.4401000