title: 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.
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.
authors.affiliation: Eicosanoids Biochemistry Section, Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Baek
authors.forename: Leigh C
authors.initials: LC
authors.lastname: Wilson
authors.forename: Linda C
authors.initials: LC
authors.lastname: Hsi
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Eling
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D015179:Colorectal Neoplasms; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D003609:Dactinomycin / Q000494:pharmacology; D051766:Early Growth Response Protein 1; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D017874:Immediate-Early Proteins; D020014:K562 Cells; D010957:Plasmids; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D012334:RNA, Neoplasm / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D000077288:Troglitazone; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D002839:Chromans; D017931:DNA Primers; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D003609:Dactinomycin; D000077288:Troglitazone