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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.
Mol Pharmacol. 2005 Nov; 68(5):1203-13.MP

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.

Authors+Show Affiliations

Section of Gastroenterology, Boston University School of medicine EBRC X-513, 650 Albany Street, Boston, MA 02118, USA. zhiyi.chen@bmc.orgNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

16077033

Citation

Chen, Zhi Yi, and Chi-Chuan Tseng. "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." Molecular Pharmacology, vol. 68, no. 5, 2005, pp. 1203-13.
Chen ZY, Tseng CC. 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. Mol Pharmacol. 2005;68(5):1203-13.
Chen, Z. Y., & Tseng, C. C. (2005). 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. Molecular Pharmacology, 68(5), 1203-13.
Chen ZY, Tseng CC. 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. Mol Pharmacol. 2005;68(5):1203-13. PubMed PMID: 16077033.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Chen,Zhi Yi, AU - Tseng,Chi-Chuan, Y1 - 2005/08/02/ PY - 2005/8/4/pubmed PY - 2005/12/13/medline PY - 2005/8/4/entrez SP - 1203 EP - 13 JF - Molecular pharmacology JO - Mol Pharmacol VL - 68 IS - 5 N2 - 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. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/16077033/15_deoxy_Delta1214_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_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16077033 DB - PRIME DP - Unbound Medicine ER -