title: Suppression of colon carcinogenesis by targeting Notch signaling.
abstract: Recent studies have shown that aberrant Notch signaling contributes to the pathogenesis of colorectal cancer (CRC). However, the potential therapeutic benefits of Notch pathway inhibitors, including gamma-secretase inhibitors (GSIs) on colon carcinogenesis are still unclear. In this study, the effects of the GSI, N-[N-3,5-difluorophenacetyl]-L-alanyl-S-phenylglycine methyl ester (DAPM) on colon carcinogenesis were investigated. In vitro, DAPM suppressed cell proliferation and induced the expression of Krüppel-like factor 4 (KLF4) and p21 in human colon cancer cells. Interestingly, p21-null HCT 116 cells were largely resistant to the suppressive effects of DAPM on cell proliferation compared with the parental cells. To investigate the effects of DAPM in vivo, colonoscopy was performed to establish the presence of colon tumors 9 weeks after azoxymethane treatment. After tumors were identified, mice were injected intraperitoneally every other day with either DAPM or vehicle for 4 weeks. The frequency of both large (>4mm) and small (<1mm) colon tumors was significantly reduced by DAPM treatment. Colon tumors in the DAPM-treated mice displayed increased levels of KLF4 and p21, accompanied by reduced Ki-67 staining compared with controls. Notably, in human colon tumor biopsies, KLF4 and p21 expressions were present within hyperplastic polyps, but the levels of both proteins were markedly reduced in tubular adenomas. Our results suggest that inhibition of Notch signaling by DAPM provides a potential chemopreventive strategy for patients with tubular adenomas, in part via activation of the KLF4-p21 axis.
authors.affiliation: Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3103, USA.
authors.forename: Shingo
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Masako
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Rosenberg
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D003111:Colonic Polyps / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C000715467:KLF4 protein, human; D019394:Ki-67 Antigen; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D051880:Receptors, Notch; C005628:DAPM; D010649:Phenylalanine; D053829:Amyloid Precursor Protein Secretases; D016283:Proto-Oncogene Proteins p21(ras)