Copland J A, Marlow L A, Kurakata S, Fujiwara K, Wong A K C, Kreinest P A, Williams S F, Haugen B R, Klopper J P, Smallridge R C
Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida 33224, USA.
Oncogene. 2006 Apr 13;25(16):2304-17. doi: 10.1038/sj.onc.1209267.
Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists demonstrate antitumor activity likely through transactivating genes that regulate cell proliferation, apoptosis, and differentiation. The PAX8/PPARgamma fusion oncogene, which is common in human follicular thyroid carcinomas appears to act via dominant negative suppression of wild-type PPARgamma, suggesting that it may be a tumor suppressor gene in thyroid cells. We have identified a novel high-affinity PPARgamma agonist (RS5444) that is dependent upon PPARgamma for its biological activity. This is the first report of this molecule and its antitumor activity. In vitro, the IC50 for growth inhibition is approximately 0.8 nM while anaplastic thyroid carcinoma (ATC) tumor growth was inhibited three- to fourfold in nude mice. siRNA against PPARgamma and a pharmacological antagonist demonstrated that functional PPARgamma was required for growth inhibitory activity of RS5444. RS5444 upregulated the cell cycle kinase inhibitor, p21WAF1/CIP1. Silencing p21WAF1/CIP1 rendered cells insensitive to RS5444. RS5444 plus paclitaxel demonstrated additive antiproliferative activity in cell culture and minimal ATC tumor growth in vivo. RS5444 did not induce apoptosis but combined with paclitaxel, doubled the apoptotic index compared to that of paclitaxel. Our data indicate that functional PPARgamma is a molecular target for therapy in ATC. We demonstrated that RS5444, a thiazolidinedione (Tzd) derivative, alone or in combination with paclitaxel, may provide therapeutic benefit to patients diagnosed with ATC.
过氧化物酶体增殖物激活受体γ（PPARγ）激动剂可能通过反式激活调节细胞增殖、凋亡和分化的基因来发挥抗肿瘤活性。PAX8/PPARγ融合致癌基因在人类滤泡性甲状腺癌中很常见，它似乎通过对野生型PPARγ的显性负性抑制起作用，这表明它可能是甲状腺细胞中的一种肿瘤抑制基因。我们鉴定出一种新型的高亲和力PPARγ激动剂（RS5444），其生物学活性依赖于PPARγ。这是关于该分子及其抗肿瘤活性的首次报道。在体外，生长抑制的IC50约为0.8 nM，而在裸鼠中，未分化甲状腺癌（ATC）的肿瘤生长受到三到四倍的抑制。针对PPARγ的小干扰RNA（siRNA）和一种药理学拮抗剂表明，RS5444的生长抑制活性需要功能性PPARγ。RS5444上调了细胞周期激酶抑制剂p21WAF1/CIP1。使p21WAF1/CIP1沉默会使细胞对RS5444不敏感。RS5444加紫杉醇在细胞培养中显示出相加的抗增殖活性，并且在体内使ATC肿瘤生长最小化。RS5444不会诱导凋亡，但与紫杉醇联合使用时，与紫杉醇相比，凋亡指数增加了一倍。我们的数据表明，功能性PPARγ是ATC治疗的分子靶点。我们证明，噻唑烷二酮（Tzd）衍生物RS5444单独使用或与紫杉醇联合使用，可能为被诊断为ATC的患者带来治疗益处。
