Troglitazone, a peroxisome proliferator-activated receptor gamma (PPAR gamma ) ligand, selectively induces the early growth response-1 gene independently of PPAR gamma. A novel mechanism for its anti-tumorigenic activity.
Troglitazone, a peroxisome proliferator-activated receptor gamma (PPAR gamma ) ligand, selectively induces the early growth response-1 gene independently of PPAR gamma. A novel mechanism for its anti-tumorigenic activity.
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发表时间：
2003
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通讯作者：
S. Baek;Leigh C. Wilson;L. Hsi;T. Eling
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作者：
S. Baek;Leigh C. Wilson;L. Hsi;T. Eling
曲格列酮（TGZ）是一种过氧化物酶体增殖物激活受体γ（PPAR γ）配体，在人结肠癌中具有促凋亡活性。尽管TGZ作为激动剂与PPAR γ转录因子结合，但新出现的证据表明TGZ在许多功能中独立于PPAR γ发挥作用，包括细胞凋亡。早期生长反应-1（Egr-1）转录因子与细胞凋亡有关，并被细胞外信号调节激酶（ERK）激活。我们研究了TGZ诱导的细胞凋亡是否可能与Egr-1诱导有关，因为已知TGZ诱导ERK活性。我们的研究结果表明，Egr-1显着诱导TGZ，但不是由其他的PPAR γ配体。TGZ至少通过两种机制影响Egr-1诱导：TGZ使Egr-1启动子活性增加2倍，使Egr-1 mRNA稳定性增加3倍。抑制HCT-116细胞中的ERK磷酸化可消除TGZ对Egr-1的诱导作用，提示其ERK依赖性方式。此外，TGZ诱导的Egr-1表达使用含有四个拷贝的Egr-1结合位点的报告系统导致启动子活性增加，并且TGZ诱导Egr-1与Egr-1共有位点的结合活性，如通过凝胶移位测定所评估的。此外，TGZ诱导PPAR γ的ERK依赖性磷酸化，导致PPAR γ活性下调。TGZ诱导的HCT-116细胞凋亡伴随着Egr-1的生物合成，这一事实表明Egr-1在TGZ诱导的HCT-116细胞凋亡中起关键作用。我们的研究结果表明，Egr-1诱导是一个独特的属性TGZ相比，其他的PPAR γ配体，是独立的PPAR γ激活。因此，Egr-1的上调可能为TGZ的抗肿瘤特性提供了解释。
Troglitazone (TGZ) is a peroxisome proliferator-activated receptor gamma (PPAR gamma) ligand that has pro-apoptotic activity in human colon cancer. Although TGZ binds to PPAR gamma transcription factors as an agonist, emerging evidence suggests that TGZ acts independently of PPAR gamma in many functions, including apoptosis. Early growth response-1 (Egr-1) transcription factor has been linked to apoptosis and shown to be activated by extracellular signal-regulated kinase (ERK). We investigated whether TGZ-induced apoptosis may be related to Egr-1 induction, because TGZ has been known to induce ERK activity. Our results show that Egr-1 is induced dramatically by TGZ but not by other PPAR gamma ligands. TGZ affects Egr-1 induction at least by two mechanisms; TGZ increases Egr-1 promoter activity by 2-fold and prolongs Egr-1 mRNA stability by 3-fold. Inhibition of ERK phosphorylation in HCT-116 cells abolishes the Egr-1 induction by TGZ, suggesting its ERK-dependent manner. Further, the TGZ-induced Egr-1 expression results in increased promoter activity using a reporter system containing four copies of Egr-1 binding sites, and TGZ induces Egr-1 binding activity to Egr-1 consensus sites as assessed by gel shift assay. In addition, TGZ induces ERK-dependent phosphorylation of PPAR gamma, resulting in the down-regulation of PPAR gamma activity. The fact that TGZ-induced apoptosis is accompanied by the biosynthesis of Egr-1 suggests that Egr-1 plays a pivotal role in TGZ-induced apoptosis in HCT-116 cells. Our results suggest that Egr-1 induction is a unique property of TGZ compared with other PPAR gamma ligands and is independent of PPAR gamma activation. Thus, the up-regulation of Egr-1 may provide an explanation for the anti-tumorigenic properties of TGZ.