Retinoid X receptor-γ and peroxisome proliferator-activated receptor-γ expression predicts thyroid carcinoma cell response to retinoid and thiazolidinedione treatment

Abstract

Abstract 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 γ (PPARγ) 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 (PPARγ−/RXRγ+), BHP 2-7 (PPARγ±/RXRγ−), and DRO-90 (RXRγ+/PPARγ+). BHP 5-16 (RXRγ+) cells treated with rexinoid had decreased proliferation to 69 ± 6% growth compared with vehicle. BHP 2-7 (PPARγ+) cells treated with thiazolidinedione had no decrease in cellular proliferation. DRO-90 (RXRγ+ and PPARγ+) 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 RXRγ and PPARγ may be necessary for maximal growth inhibition by ligands and may be required for the increased apoptosis.