QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.105.014944v1 68/5/1203    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, Z. Y. Articles by Tseng, C.-C. Search for Related Content PubMed PubMed Citation Articles by Chen, Z. Y. Articles by Tseng, C.-C.

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.

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

This article has been cited by other articles:

				S. D. Cho, S. Chintharlapalli, M. Abdelrahim, S. Papineni, S. Liu, J. Guo, P. Lei, A. Abudayyeh, and S. Safe 5,5'-Dibromo-bis(3'-indolyl)methane induces Kruppel-like factor 4 and p21 in colon cancer cells Mol. Cancer Ther., July 1, 2008; 7(7): 2109 - 2120. [Abstract] [Full Text] [PDF]

				S. Chintharlapalli, S. Papineni, I. Jutooru, A. McAlees, and S. Safe Structure-dependent activity of glycyrrhetinic acid derivatives as peroxisome proliferator-activated receptor {gamma} agonists in colon cancer cells Mol. Cancer Ther., May 1, 2007; 6(5): 1588 - 1598. [Abstract] [Full Text] [PDF]

				Y. Zeng, S. Zhuang, J. Gloddek, C.-C. Tseng, G. R. Boss, and R. B. Pilz Regulation of cGMP-dependent Protein Kinase Expression by Rho and Kruppel-like Transcription Factor-4 J. Biol. Chem., June 23, 2006; 281(25): 16951 - 16961. [Abstract] [Full Text] [PDF]

				O. Schroder, Y. Yudina, A. Sabirsh, N. Zahn, J. Z. Haeggstrom, and J. Stein 15-deoxy-{Delta}12,14-prostaglandin J2 inhibits the expression of microsomal prostaglandin E synthase type 2 in colon cancer cells J. Lipid Res., May 1, 2006; 47(5): 1071 - 1080. [Abstract] [Full Text] [PDF]

				M. A. Peraza, A. D. Burdick, H. E. Marin, F. J. Gonzalez, and J. M. Peters The Toxicology of Ligands for Peroxisome Proliferator-Activated Receptors (PPAR) Toxicol. Sci., April 1, 2006; 90(2): 269 - 295. [Abstract] [Full Text] [PDF]