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Molecular Pharmacology

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Research ArticleArticle

15-Deoxy-Δ12,14 Prostaglandin J2 Up-Regulates Krüppel-Like Factor 4 Expression Independently of Peroxisome Proliferator-Activated Receptor γ by Activating the Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Signal Transduction Pathway in HT-29 Colon Cancer Cells

Zhi Yi Chen and Chi-Chuan Tseng
Molecular Pharmacology November 2005, 68 (5) 1203-1213; DOI: https://doi.org/10.1124/mol.105.014944
Zhi Yi Chen
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Chi-Chuan Tseng
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Abstract

15-Deoxy-Δ12,14 prostaglandin J2 (15d-PGJ2) is a natural ligand for the peroxisome proliferator-activated receptor γ (PPARγ) that exhibits antiproliferative activity in colon cancer cells, but its mechanism of action is still poorly understood. In this study, we showed that Krüppel-like factor 4 (KLF4) is one of the downstream effectors of 15d-PGJ2. Treatment of HT-29 cells with 15d-PGJ2 resulted in up-regulation of both KLF4 mRNA and protein expression, and these increases were also observed in other colon cancer cell lines. Down-regulation of KLF4 expression by small interfering RNA (siRNA) targeting KLF4 reduced 15d-PGJ2-mediated G1 phase arrest, suggesting that KLF4-mediated function of 15d-PGJ2. The effect of 15d-PGJ2 on KLF4 expression seems not to involve its nuclear receptor PPARγ, in that our data show that:1) KLF4 gene promoter does not contain putative PPRE sequence, 2) 15d-PGJ2 rapidly activates extracellular signal-regulated kinase (ERK) and induces KLF4 mRNA expression, 3) KLF4 is induced by 15d-PGJ2 but not by rosiglitazone, a synthetic PPARγ ligand, and 4) 15d-PGJ2 is unable to stimulate PPAR-dependent promoter activity in the absence of cotransfected PPARγ. Moreover, 15d-PGJ2-mediated KLF4 mRNA expression was blocked by 2′-amino-3′-methoxyflavone (PD98059) or 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126), two ERK kinase MAP inhibitors, whereas the phosphoinositol-3 kinase inhibitors wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) had no such effect. Furthermore, KLF4 induction by 15d-PGJ2 occurred only in signal transducer and activator of transcription 1 (STAT1)-expressing, not in STAT1-knockout cells. Together, these results suggest that 15d-PGJ2-induced growth inhibition of colon cancer cells is mediated, at least in part, through up-regulation of KLF4 expression. This induction is unlikely to be mediated through the PPARγ receptor but may involve the mitogen-activated protein kinase kinase/ERK pathway and is STAT1-dependent.

  • Received May 19, 2005.
  • Accepted August 2, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 68 (5)
Molecular Pharmacology
Vol. 68, Issue 5
1 Nov 2005
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15-Deoxy-Δ12,14 Prostaglandin J2 Up-Regulates Krüppel-Like Factor 4 Expression Independently of Peroxisome Proliferator-Activated Receptor γ by Activating the Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Signal Transducti…
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Research ArticleArticle

15-Deoxy-Δ12,14 Prostaglandin J2 Up-Regulates Krüppel-Like Factor 4 Expression Independently of Peroxisome Proliferator-Activated Receptor γ by Activating the Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Signal Transduction Pathway in HT-29 Colon Cancer Cells

Zhi Yi Chen and Chi-Chuan Tseng
Molecular Pharmacology November 1, 2005, 68 (5) 1203-1213; DOI: https://doi.org/10.1124/mol.105.014944

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Research ArticleArticle

15-Deoxy-Δ12,14 Prostaglandin J2 Up-Regulates Krüppel-Like Factor 4 Expression Independently of Peroxisome Proliferator-Activated Receptor γ by Activating the Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Signal Transduction Pathway in HT-29 Colon Cancer Cells

Zhi Yi Chen and Chi-Chuan Tseng
Molecular Pharmacology November 1, 2005, 68 (5) 1203-1213; DOI: https://doi.org/10.1124/mol.105.014944
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