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15-Deoxy-^12,14 Prostaglandin J₂ Up-Regulates Krüppel-Like Factor 4 Expression Independently of Peroxisome Proliferator-Activated Receptor by Activating the Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Signal Transduction Pathway in HT-29 Colon Cancer Cells

Section of Gastroenterology, VA Boston Healthcare System and Boston University School of Medicine, Boston, Massachusetts

15-Deoxy-^12,14 prostaglandin J₂ (15d-PGJ₂) is a natural ligand for the peroxisome proliferator-activated receptor (PPAR) 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 PPAR, 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 PPAR ligand, and 4) 15d-PGJ₂ is unable to stimulate PPAR-dependent promoter activity in the absence of cotransfected PPAR. 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 PPAR receptor but may involve the mitogen-activated protein kinase kinase/ERK pathway and is STAT1-dependent.

Received for publication May 19, 2005.

Accepted for publication August 2, 2005.

Address correspondence to: Dr. Zhi Yi Chen, Section of Gastroenterology, Boston University School of medicine EBRC X-513, 650 Albany Street, Boston, MA 02118. E-mail: zhiyi.chen{at}bmc.org

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