title: Inhibition of colorectal cancer by targeting hepatocyte nuclear factor-4alpha.
abstract: Hepatocyte nuclear factor-4alpha (HNF-4alpha) 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-4alpha in CRC has been verified here by evaluating the effect of HNF-4alpha antagonists and HNF-4alpha siRNA on CRC growth and proliferation in cultured CRC cells and xenotransplanted nude mice in vivo. HNF-4alpha ligand antagonists of the MEDICA series, namely, beta,beta'-tetramethylhexadecanedioic acid (M16betabeta) and gamma,gamma'-tetramethyloctadocanedioic acid (M18gammagamma) as well as HNF-4alpha 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-4alpha ligand antagonists and by HNF-4alpha siRNA was accounted for by suppression of HNF-4alpha transcription and protein expression. alpha,alpha'-tetrachlorotetradecanedioic acid (Cl-DICA), a MEDICA analogue that fails to suppress HNF-4alpha, was ineffective in suppressing growth of cultured or xenotransplanted HT29 CRC cells. Hence, increased transcriptional activity of HNF-4alpha converging onto genes coding for antiapoptotic oncogenes and cytokines may promote CRC development. Suppression of HNF-4alpha activity by natural or xenobiotic HNF-4alpha ligand antagonists or by HNF-4alpha siRNA may offer a treatment mode for CRC.
authors.affiliation: The Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel. bschwart@agri.huji.ac.il
authors.forename: Betty
authors.initials: B
authors.lastname: Schwartz
authors.forename: Anna
authors.initials: A
authors.lastname: Algamas-Dimantov
authors.forename: Rachel
authors.initials: R
authors.lastname: Hertz
authors.forename: Jennifer
authors.initials: J
authors.lastname: Nataf
authors.forename: Ayelet
authors.initials: A
authors.lastname: Kerman
authors.forename: Irena
authors.initials: I
authors.lastname: Peri
authors.forename: Jacob
authors.initials: J
authors.lastname: Bar-Tana
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002839:Chromans / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000473:pathology / Q000628:therapy*; D019073:HT29 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D047495:PPAR gamma / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone
chemical_list: D002839:Chromans; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D047495:PPAR gamma; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D000077288:Troglitazone