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¹ Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado and ² Department of Medicine, West Los Angeles VAMC and University of California School of Medicine, Los Angeles, California

Requests for reprints: Joshua P. Klopper, Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Cancer Center, University of Colorado Health Sciences Center, Box B151, 4200 East 9th Avenue, Denver, CO 80262. Phone: 303-315-8443; Fax: 303-315-4525. E-mail: joshua.klopper{at}uchsc.edu

Poorly differentiated, metastatic thyroid cancer is difficult to treat. These tumors often do not concentrate radioactive iodine and may require chemotherapy, which is suboptimal and toxic. Nuclear hormone receptors peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor (RXR) are variably expressed in thyroid carcinoma cell lines. Expression of these receptors may predict thyroid cancer cell response to treatment with rexinoids and thiazolidinediones. We studied three thyroid carcinoma cell lines: BHP 5-16 (PPAR–/RXR+), BHP 2-7 (PPAR±/RXR–), and DRO-90 (RXR+/PPAR+). BHP 5-16 (RXR+) cells treated with rexinoid had decreased proliferation to 69 ± 6% growth compared with vehicle. BHP 2-7 (PPAR+) cells treated with thiazolidinedione had no decrease in cellular proliferation. DRO-90 (RXR+ and PPAR+) cells had 36 ± 10%, 15 ± 3%, and 13 ± 4% growth when treated with rexinoid, thiazolidinedione, or a combination, respectively. We next investigated the role of apoptosis in the ligand-responsive BHP 5-16 and DRO-90 cells. BHP 5-16 cells underwent no significant apoptosis with rexinoid (1 µmol/L). DRO-90 cells, however, had 3.6 ± 1.3% apoptotic cells with vehicle, 13 ± 3.5% with rexinoid (1 µmol/L), 18 ± 4% with thiazolidinedione (1 µmol/L), and 28 ± 6% with combination treatment (1 µmol/L), suggesting that apoptosis plays a major role in this anaplastic cell line and that the effects of the two ligands are additive. We conclude that receptor expression is necessary for inhibition of thyroid carcinoma growth with ligand treatment but may not be sufficient for response. Additionally, expression of both RXR and PPAR may be necessary for maximal growth inhibition by ligands and may be required for the increased apoptosis.

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Received 3/ 3/04; revised 5/24/04; accepted 6/17/04.