MCC-555-induced NAG-1 expression is mediated in part by KLF4.

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a central role in cell differentiation, metabolism and tumorigenesis. We have investigated the therapeutic properties of 5-[[6-[(2-fluorophenyl)-methoxy]-2-napthalenyl]-methyl]-2,4-thiazolidinedione (MCC-555) a PPARgamma agonist in human colorectal cancer cells. To elucidate the molecular mechanism(s), by which MCC-555 exerts its effects on the human colorectal cancer cells, we have analyzed the expression of two pro-apoptotic proteins, Krüppel-like factor 4 (KLF4) and nonsteroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1). MCC-555-induced expression of the transcription factor, KLF-4 was blocked by a PPARgamma specific antagonist GW9662 in PPARgamma-dependent manner in HCT-116 cells. We further identified a new KLF4 target gene NAG-1, which shows a pro-apoptotic activity. We confirmed that PPARgamma agonists-induced NAG-1 expression was abolished using KLF4 siRNA in HCT-116 cells. Subsequently, KLF4 expression enhances the NAG-1 promoter activity in HCT-116 cells, and functional KLF4 binding sites in the NAG-1 promoter were also identified. MCC-555, a PPARgamma agonist induced the expression of Klf4 mRNA and protein in murine intestinal tumors from MCC-555-treated mice, as assessed by RT-PCR and immunohistochemistry. This study shows that PPARgamma agonists up-regulate KLF4 expression in receptor-dependent manner, and KLF4 was identified as a novel transcription factor that controls NAG-1 promoter activity in human and mouse colorectal cancers.

• Authors: Maria Cekanova, Seong-Ho Lee, Michael F McEntee, Seung Joon Baek
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 637 Issue 1-3 Pg. 30-7 (Jul 10 2010) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 20385121 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Growth Inhibitors
• KLF4 protein, human
• Klf4 protein, mouse
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors
• NBAS protein, human
• Neoplasm Proteins
• PPAR gamma
• RNA, Messenger
• Thiazolidinediones
• Transcription Factors
• 2,4-thiazolidinedione
• netoglitazone

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Colorectal Neoplasms (genetics, metabolism, pathology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Growth Inhibitors (pharmacology)
• HCT116 Cells
• Humans
• Immunohistochemistry
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors (genetics, metabolism)
• Mice
• Neoplasm Proteins (biosynthesis, genetics)
• PPAR gamma (agonists, antagonists & inhibitors, metabolism)
• RNA, Messenger (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Thiazolidinediones (pharmacology)
• Transcription Factors (metabolism)
• Up-Regulation (drug effects)