title: Liver X receptors inhibit proliferation of human colorectal cancer cells and growth of intestinal tumors in mice.
abstract: OBJECTIVE
  Liver X receptors (LXRs) are transcriptional regulators of cholesterol metabolism, controlling cholesterol flow into cells, catabolism, and efflux. Cholesterol controls cell proliferation; disruptions in cholesterol metabolism have been associated with the development of colon cancer. We investigated whether expression of activated LXR protects against intestinal tumorigenesis in mice.
  
  
  METHODS
  We analyzed the development of colon cancer in mice that express a constitutive active form of LXRα only in the intestinal epithelium, under the control of villin promoter (iVP16LXRα). These mice were crossed with adenomatous polyposis coli (Apc)(min/+) mice, or given azoxymethane followed by dextran sodium sulfate, to assess intestinal tumor formation. We also assessed proliferation and apoptosis of a human colorectal cancer cell line (HT29) transfected with an adenoviral vector that expressed Ad VP16hLXRα, compared with cells expressing AdVP16 (control), and their ability to form xenograft tumors in mice. HT29 cells also were incubated with the LXR ligand GW3965.
  
  
  RESULTS
  In human colorectal cancer cells, ligand-induced activation of LXR or transfection with Ad VP16hLXRα blocked the G1 phase, increased caspase-dependent apoptosis, and slowed growth of xenograft tumors in mice. iVP16LXRα mice formed fewer, smaller tumors than VP16 (control) mice after administration of azoxymethane and dextran sodium sulfate. APC(min/+)/iVP16LXRα mice also developed fewer, smaller intestinal tumors than APC(min/+)/iVP16 mice. Gene expression analysis indicated that activation of LXRα affected lipid metabolic networks and increased cholesterol efflux in the intestine.
  
  
  CONCLUSIONS
  Expression of activated LXRα blocks proliferation of human colorectal cancer cells and slows the growth of xenograft tumors in mice. It also reduces intestinal tumor formation after administration of chemical carcinogens, and in Apc(min/+) mice. LXR agonists therefore might be developed as therapeutic treatments for colorectal cancer.
authors: Laboratory of Lipid Metabolism and Cancer, Department of Translational Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy.
authors: Giuseppe
authors: G
authors: Lo Sasso
authors: Fabiola
authors: F
authors: Bovenga
authors: Stefania
authors: S
authors: Murzilli
authors: Lorena
authors: L
authors: Salvatore
authors: Giuseppe
authors: G
authors: Di Tullio
authors: Nicola
authors: N
authors: Martelli
authors: Andria
authors: A
authors: D'Orazio
authors: Stefania
authors: S
authors: Rainaldi
authors: Michele
authors: M
authors: Vacca
authors: Anita
authors: A
authors: Mangia
authors: Giuseppe
authors: G
authors: Palasciano
authors: Antonio
authors: A
authors: Moschetta
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000236:Adenoma / Q000503:physiopathology*; D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D017491:Genes, APC; D019073:HT29 Cells; D006801:Humans; D007414:Intestinal Neoplasms / Q000378:metabolism* / Q000473:pathology; D000071518:Liver X Receptors; D051379:Mice; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors