Abstract
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.
Highlights
From the Eicosanoids Biochemistry Section, Laboratory of Molecular Carcinogenesis, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709
The anti-tumorigenic activities of peroxisome proliferator-activated receptors (PPARs)␥ ligands are well established in human cancer, controversy exists in the literature with regard to the relative contributions of nuclear receptor-dependent [13, 41, 42] and -independent mechanisms [43,44,45]
We demonstrate that troglitazone, a PPAR␥ agonist, induces human colorectal cancer cells to undergo apoptosis and inhibits their growth on soft agar
Summary
From the Eicosanoids Biochemistry Section, Laboratory of Molecular Carcinogenesis, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709. TGZ binds to PPAR␥ transcription factors as an agonist, emerging evidence suggests that TGZ acts independently of PPAR␥ in many functions, including apoptosis. Our results suggest that Egr-1 induction is a unique property of TGZ compared with other PPAR␥ ligands and is independent of PPAR␥ activation. PPAR␥ ligands are able to bind to the PPAR␥ transcription factor, which forms a heterodimeric complex with retinoid X receptor that functions as a central regulator of differentiation, and modulator of cell growth. TGZ up-regulates nitric oxide synthesis [14], induces the p53 pathway [15], inhibits cholesterol biosynthesis [16], induces p21 cyclin-dependent kinase inhibitor [17], has antioxidant function [18], and activates extracellular signal-regulated protein kinase (ERK) [19] in a PPAR␥-independent manner. The molecular mechanism of TGZ-induced anti-tumorigenesis may result from multiple mechanisms
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