Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor
Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor
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DOI：
10.1073/pnas.94.1.237
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发表时间：
1997-01-07
影响因子：
11.1
通讯作者：
Spiegelman, BM
中科院分区：
文献类型：
--
作者：
Tontonoz, P;Singer, S;Spiegelman, BM
诱导终末分化是治疗某些人类恶性肿瘤的一种很有前途的方法。过氧化物酶体增殖物激活受体γ(PPARγ)和维甲酸X受体α(RXRα)形成异源二聚体复合体，发挥脂肪细胞分化的中央调节作用。已经确定了这两种受体的天然和合成配体。我们在这里证明了PPARγ在人类脂肪肉瘤的每一种主要组织学类型中都有高水平的表达。此外，原代人类脂肪肉瘤细胞可以被PPARγ配体PIOGLITA-zone诱导向终末分化，这表明这些细胞的分化障碍可以通过最大限度地激活PPAR途径来克服。我们进一步证明，RXR特异性配体也是表达PPARγ/RXRα异源二聚体的细胞的有效成脂剂，同时用PPARγ和RXR特异性配体处理脂肪肉瘤细胞可以产生相加的分化刺激。脂肪肉瘤细胞分化的特征是细胞内脂质的积聚，脂肪细胞特异性基因的诱导，以及退出细胞周期。这些结果表明，PPAR的伽马配体，如噻唑烷二酮类和RXR特异性维甲酸类化合物，可能是治疗脂肪肉瘤的有用药物。
Induction of terminal differentiation represents a promising therapeutic approach to certain human malignancies. The peroxisome proliferator-activated receptor gamma (PPAR gamma) and the retinoid X receptor alpha (RXR alpha) form a heterodimeric complex that functions as a central regulator of adipocyte differentiation. Natural and synthetic ligands for both receptors have been identified. We demonstrate here that PPAR gamma is expressed at high levels in each of the major histologic types of human liposarcoma. Moreover, primary human liposarcoma cells can be induced to undergo terminal differentiation by treatment with the PPAR gamma ligand pioglita-zone, suggesting that the differentiation block in these cells can be overcome by maximal activation of the PPAR pathway, We further demonstrate that RXR-specific ligands are also potent adipogenic agents in cells expressing the PPAR gamma/RXR alpha heterodimer, and that simultaneous treatment of liposarcoma cells with both PPAR gamma- and RXR-specific ligands results in an additive stimulation of differentiation. Liposarcoma cell differentiation is characterized by accumulation of intracellular lipid, induction of adipocyte-specific genes, and withdrawl from the cell cycle. These results suggest that PPAR gamma ligands such as thiazolidinediones and RXR-specific retinoids may be useful therapeutic agents for the treatment of liposarcoma.