Inhibition of colorectal cancer by targeting hepatocyte nuclear factor-4α

✍ Scribed by Betty Schwartz; Anna Algamas-Dimantov; Rachel Hertz; Jennifer Nataf; Ayelet Kerman; Irena Peri; Jacob Bar-Tana

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: French
• Weight: 455 KB
• Volume: 124
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.24041

✦ Synopsis

Abstract

Hepatocyte nuclear factor‐4α (HNF‐4α) serves as target for fatty acid nutrients and xenobiotic amphipathic carboxylates and may account for the differential effects of dietary fatty acids on colorectal cancer (CRC). The putative role played by HNF‐4α in CRC has been verified here by evaluating the effect of HNF‐4α antagonists and HNF‐4α siRNA on CRC growth and proliferation in cultured CRC cells and xenotransplanted nude mice in vivo. HNF‐4α ligand antagonists of the MEDICA series, namely, β,β'‐tetramethylhexadecanedioic acid (M16ββ) and γ,γ'‐tetramethyloctadocanedioic acid (M18γγ) as well as HNF‐4α siRNA are shown here to inhibit growth and proliferation of HT29 and Caco2 CRC cells, accompanied by increased subG1 cell population, downregulated PCNA, activation of caspase‐3, upregulation of Bak and cytoplasmic cytochrome‐c, and downregulation of Bcl‐2 resulting in apoptotic death. Inhibition of CRC growth with concomitant apoptosis was further confirmed in nude mice xenotransplanted with HT29 CRC cells. CRC suppression by HNF‐4α ligand antagonists and by HNF‐4α siRNA was accounted for by suppression of HNF‐4α transcription and protein expression. α,α'‐tetrachlorotetradecanedioic acid (Cl‐DICA), a MEDICA analogue that fails to suppress HNF‐4α, was ineffective in suppressing growth of cultured or xenotransplanted HT29 CRC cells. Hence, increased transcriptional activity of HNF‐4α converging onto genes coding for antiapoptotic oncogenes and cytokines may promote CRC development. Suppression of HNF‐4α activity by natural or xenobiotic HNF‐4α ligand antagonists or by HNF‐4α siRNA may offer a treatment mode for CRC. © 2008 Wiley‐Liss, Inc.