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

Betty Schwartz*, Anna Algamas-Dimantav, Rachel Hertz, Jennifer Natal, Ayelet Kerman, Irena Peri, Jacob Bar-Tana

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

Hepatocyte nuclear factor-4a (HNF-4α) serves as target for fatty acid nutrients and xenobiotic amphipathie 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,'-tetrame-thylhexadeeanedioic acid (Ml16ββ) and γ',γ-tetraniethyloctadoca- nedioic acid (M18γ,γ) as well as HNF-4α siRNA are shown here to inhibit growth and proliferation of HT29 and Caeo2 CRC cells, accompanied by increased subGl cell population, downregulated PCNA, activation of caspase-3, upregulation of Bak and cytoplasmic cytochrome-c, and downregulation of BcI-2 resulting in apo-ptotic death. Inhibition of CRC growth with concomitant apopto-sis 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-4a transcription and protein expression. a,α-tetrachlorotetrade- canedioic acid (CI-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 antia-poptotic 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.

Original languageAmerican English
Pages (from-to)1081-1089
Number of pages9
JournalInternational Journal of Cancer
Volume124
Issue number5
DOIs
StatePublished - 1 Mar 2009

Keywords

  • Colorectal cancer
  • HNF-4α
  • Long chain fatty acids

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