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15-deoxy-Delta12,14 prostaglandin J2 up-regulates Kruppel-like factor 4 expression independently of peroxisome proliferator-activated receptor gamma by activating the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signal transduction pathway in HT-29 colon cancer cells.

Abstract
15-Deoxy-Delta(12,14) prostaglandin J2 (15d-PGJ2) is a natural ligand for the peroxisome proliferator-activated receptor gamma (PPARgamma) 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 PPARgamma, 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 PPARgamma ligand, and 4) 15d-PGJ2 is unable to stimulate PPAR-dependent promoter activity in the absence of cotransfected PPARgamma. 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 PPARgamma receptor but may involve the mitogen-activated protein kinase kinase/ERK pathway and is STAT1-dependent.
AuthorsZhi Yi Chen, Chi-Chuan Tseng
JournalMolecular pharmacology (Mol Pharmacol) Vol. 68 Issue 5 Pg. 1203-13 (Nov 2005) ISSN: 0026-895X [Print] United States
PMID16077033 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • 15-deoxyprostaglandin J2
  • KLF4 protein, human
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors
  • PPAR gamma
  • RNA, Messenger
  • RNA, Small Interfering
  • DNA
  • Extracellular Signal-Regulated MAP Kinases
  • Prostaglandin D2
Topics
  • Caco-2 Cells
  • Cell Proliferation (drug effects)
  • Colonic Neoplasms (metabolism, pathology)
  • DNA (biosynthesis)
  • Extracellular Signal-Regulated MAP Kinases (physiology)
  • G1 Phase
  • Gene Expression Regulation (drug effects)
  • HT29 Cells
  • Humans
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors (genetics)
  • MAP Kinase Signaling System (physiology)
  • PPAR gamma (physiology)
  • Phosphorylation
  • Prostaglandin D2 (analogs & derivatives, pharmacology)
  • RNA, Messenger (analysis)
  • RNA, Small Interfering (pharmacology)
  • Up-Regulation

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