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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 5 2170-2177
Copyright © 2001 by The Endocrine Society

Original Studies

Ligands for Peroxisome Proliferator-Activated Receptor {gamma} Inhibit Growth and Induce Apoptosis of Human Papillary Thyroid Carcinoma Cells

Kazuyasu Ohta, Toyoshi Endo, Kazutaka Haraguchi, Jerome M. Hershman and Toshimasa Onaya

Third Department of Internal Medicine (K.O., T.E., K.H., T.O.), Yamanashi Medical University, Yamanashi 409-3898, Japan; and Endocrine Research Laboratory (J.M.H.), West Los Angeles Veterans Affairs Medical Center and University of California School of Medicine, Los Angeles, California 90073

Address all correspondence and requests for reprints to: Toshimasa Onaya, M.D., Third Department of Internal Medicine, Yamanashi Medical University, 1110 Shimo-Kato Tamaho, Yamanashi, 409-3898 Japan. E-mail: onayat{at}res.yamanashi-med.ac.jp

Ligands for peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) induce apoptosis and exert antiproliferative effects on several carcinoma cell lines. The present study investigates the expression of PPAR{gamma} and the possibility that agonists for PPAR{gamma} also inhibit the growth of human thyroid carcinoma cells. We examined this hypothesis using six cell lines, designated BHP thyroid carcinoma cells, which originated from patients with papillary thyroid carcinoma. RT-PCR analysis revealed that the thyroid carcinoma cell lines BHP2–7, 7–13, 10–3, and 18–21 express PPAR{gamma}. More PPAR{gamma} was expressed in carcinoma than in adjacent normal thyroid tissue in three of six samples of human papillary carcinoma of the thyroid.

PPAR{gamma}-positive thyroid carcinoma cells were treated with agonists of PPAR{gamma}, troglitazone, BRL 49653, and 15-deoxy-{Delta}12,14-prostaglandin J2. Troglitazone (10 µmol/L), BRL 49653 (10 µmol/L), and 15-deoxy-{Delta}12,14-prostaglandin J2 (1 µg/mL) decreased [3H]thymidine incorporation and reduced cell number, respectively, in BHP carcinoma cell lines that expressed PPAR{gamma}. Under low serum conditions, ligands for PPAR{gamma} induced condensation of the nucleus and fragmentation of chromatin into nucleosome ladders. These findings indicate that the death of thyroid carcinoma cells is a form of apoptosis.

To investigate the molecular mechanism of the apoptosis, we assessed expression of the apoptosis-regulatory genes bcl-2, bax, and c-myc. Troglitazone significantly increased the expression of c-myc messenger RNA but had no effect on the expression of bcl-2 and bax in thyroid carcinoma cells. These results suggest that, at least in part, the induction of apoptosis in human papillary thyroid carcinoma cells may be due to an increase of c-myc.

Troglitazone (500 mg/kg·day) significantly inhibited tumor growth and prevented distant metastasis of BHP18–21 tumors in nude mice in vivo.

Taken together, these results suggest that PPAR{gamma} agonist inhibit cell growth of some types of human thyroid cancer.




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