A peroxisome proliferator-activated receptor ligand MCC-555 imparts anti-proliferative response in pancreatic cancer cells by PPARgamma-independent up-regulation of KLF4.

Abstract

MCC-555 is a novel PPARα/γ dual ligand of the thiazolidinedione class and was recently developed as an anti-diabetic drug with unique properties. MCC-555 also has anti-proliferative activity through growth inhibition and apoptosis induction in several cancer cell types. Our group has shown that MCC-555 targets several proteins in colorectal tumorigenesis including nonsteroidal anti-inflammatory drug (NSAID)-activated gene (NAG-1) which plays an important role in chemoprevention responsible for chemopreventive compounds. NAG-1 is a member of the TGF-β superfamily and is involved in tumor progression and development; however, NAG-1's roles in pancreatic cancer have not been studied. In this report, we found that MCC-555 alters not only NAG-1 expression, but also p21 and cyclin D1 expression. NAG-1 and p21 expression was not blocked by PPARγ-specific antagonist GW9662, suggesting that MCC-555-induced NAG-1 and p21 expression is independent of PPARγ activation. However, decreasing cyclin D1 by MCC-555 seems to be affected by PPARγ activation. Further, we found that the GC box located in the NAG-1 promoter play an important role in NAG-1 transactivation by MCC-555. Subsequently, we screened several transcription factors that may bind to the GC box region in the NAG-1 promoter and found that KLF4 potentially binds to this region. Expression of KLF4 precedes NAG-1 and p21 expression in the presence of MCC-555, whereas blocking KLF4 expression using specific KLF4 siRNA showed that both NAG-1 and p21 expression by MCC-555 was blocked. In conclusion, MCC-555's actions on anti-proliferation involve both PPARγ-dependent and -independent pathways, thereby enhancing anti-tumorigenesis in pancreatic cancer cells.

• Authors: Kyung-Won Min, Xiaobo Zhang, Temjenmongla Imchen, Seung Joon Baek
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 263 Issue 2 Pg. 225-32 (Sep 01 2012) ISSN: 1096-0333 [Electronic] United States
• PMID: 22750490 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• 2-chloro-5-nitrobenzanilide
• Anilides
• Antineoplastic Agents
• Cyclin-Dependent Kinase Inhibitor p21
• GDF15 protein, human
• Growth Differentiation Factor 15
• KLF4 protein, human
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors
• PPAR gamma
• Thiazolidinediones
• netoglitazone

Topics

• Anilides (pharmacology)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Growth Differentiation Factor 15 (genetics)
• Humans
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors (genetics)
• PPAR gamma (agonists)
• Pancreatic Neoplasms (drug therapy, pathology)
• Thiazolidinediones (pharmacology)
• Up-Regulation (drug effects)