Abstract
The peroxisome proliferator-activated receptor γ (PPAR γ), 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 γ and its activation by natural ligand (15-deoxy-Δ12,14 - prostaglandin J2) 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 γ-mediated apoptosis and down-regulation of the c-myc gene expression.
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Abbreviations
- PPAR:
-
peroxisome proliferator-activated receptor
- Tcf-4:
-
T cell factor-4
- APC:
-
adenomatous polyposis coli
- FCS:
-
fetal calf serum
- EMSA:
-
electrophoretic mobility shift assay
- ECL:
-
enhanced chemiluminescence
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Yamakawa-Karakida, N., Sugita, K., Inukai, T. et al. Ligand activation of peroxisome proliferator-activated receptor γ induces apoptosis of leukemia cells by down-regulating the c-myc gene expression via blockade of the Tcf-4 activity. Cell Death Differ 9, 513–526 (2002). https://doi.org/10.1038/sj.cdd.4401000
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DOI: https://doi.org/10.1038/sj.cdd.4401000
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