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

• Published in: Cell death and differentiation Vol. 9; no. 5; pp. 513 - 526
• Main Authors: Yamakawa-Karakida, N, Sugita, K, Inukai, T, Goi, K, Nakamura, M, Uno, K, Sato, H, Kagami, K, Barker, N, Nakazawa, S
• Format: Journal Article
• Language: English
• Published: England 01.05.2002
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - physiology; Caspase 3; Caspases - metabolism; 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 - biosynthesis; Proto-Oncogene Proteins c-myc - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Cytoplasmic and Nuclear - physiology; RNA, Messenger - biosynthesis; TCF Transcription Factors; Thiazoles - pharmacology; Thiazolidinediones; Transcription Factor 7-Like 2 Protein; Transcription Factors - metabolism; Transcription Factors - physiology; Troglitazone; Tumor Cells, Cultured
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/sj.cdd.4401000

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.