The PPARγ ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells.
The PPARγ ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells.
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DOI：
10.1016/j.yexcr.2010.09.015
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发表时间：
2010-12-10
影响因子：
3.7
通讯作者：
Stewart LV
中科院分区：
文献类型：
--
作者：
Moss PE;Lyles BE;Stewart LV
雄激素受体（AR）调节雄激素依赖性和雄激素非依赖性前列腺癌细胞的生长和进展。据报道，过氧化物酶体增殖物激活受体γ（PPARγ）激动剂可降低雄激素依赖性LNCaP前列腺癌细胞中的AR激活。为了确定PPARγ配体在抑制雄激素非依赖性前列腺癌中的AR活性方面是否同样有效，我们检查了PPARγ配体环格列酮和罗格列酮对C4-2细胞（LNCaP细胞系的雄激素非依赖性衍生物）的作用。基于荧光素酶的报告基因分析和Western印迹分析表明，在LNCaP细胞中，PPARγ配体减少了双氢睾酮（DHT）诱导的AR活性增加。然而，在C4-2细胞中，这些化合物增加了DHT诱导的AR驱动的荧光素酶活性。此外，ciglitazone没有显著改变DHT介导的C4-2细胞内前列腺特异性抗原（PSA）蛋白或mRNA水平的增加。基于siRNA的实验表明，C4-2细胞中观察到的环格列酮诱导的AR活性调节依赖于PPARγ的存在。此外，AR辅阻遏物细胞周期蛋白D1的过表达抑制了环格列酮诱导C4-2细胞中AR荧光素酶活性的能力。因此，我们的数据表明，在雄激素非依赖性C4-2前列腺癌细胞中，PPARγ和细胞周期蛋白D1水平影响环格列酮差异调节AR信号的能力。
The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator activated receptor gamma (PPARγ) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPARγ ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPARγ ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated PPARγ ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPARγ. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest both PPARγ and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.
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影响因子：
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