Liver X receptors inhibit proliferation of human colorectal cancer cells and growth of intestinal tumors in mice

Giuseppe Lo Sasso, Fabiola Bovenga, Stefania Murzilli, Lorena Salvatore, Giuseppe Di Tullio, Nicola Martelli, Andria D'Orazio, Stefania Rainaldi, Michele Vacca, Anita Mangia, Giuseppe Palasciano, Antonio Moschetta

Research output: Contribution to journalArticle

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Abstract

Background & Aims: 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. APCmin/+/iVP16LXRα mice also developed fewer, smaller intestinal tumors than APCmin/+/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.

Original languageEnglish (US)
JournalGastroenterology
Volume144
Issue number7
DOIs
StatePublished - Jun 2013

Fingerprint

Colorectal Neoplasms
Growth
Neoplasms
Cholesterol
Heterografts
Azoxymethane
Dextran Sulfate
Adenomatous Polyposis Coli
Colonic Neoplasms
Liver X Receptors
Apoptosis
Ligands
Activation Analysis
HT29 Cells
G1 Phase
Intestinal Mucosa
Caspases
Metabolic Networks and Pathways
Carcinogens
Intestines

Keywords

  • Adenoma
  • Mouse Model
  • NR1H3/NR1H2
  • Nuclear Receptor

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Lo Sasso, G., Bovenga, F., Murzilli, S., Salvatore, L., Di Tullio, G., Martelli, N., ... Moschetta, A. (2013). Liver X receptors inhibit proliferation of human colorectal cancer cells and growth of intestinal tumors in mice. Gastroenterology, 144(7). https://doi.org/10.1053/j.gastro.2013.02.005

Liver X receptors inhibit proliferation of human colorectal cancer cells and growth of intestinal tumors in mice. / Lo Sasso, Giuseppe; Bovenga, Fabiola; Murzilli, Stefania; Salvatore, Lorena; Di Tullio, Giuseppe; Martelli, Nicola; D'Orazio, Andria; Rainaldi, Stefania; Vacca, Michele; Mangia, Anita; Palasciano, Giuseppe; Moschetta, Antonio.

In: Gastroenterology, Vol. 144, No. 7, 06.2013.

Research output: Contribution to journalArticle

Lo Sasso, G, Bovenga, F, Murzilli, S, Salvatore, L, Di Tullio, G, Martelli, N, D'Orazio, A, Rainaldi, S, Vacca, M, Mangia, A, Palasciano, G & Moschetta, A 2013, 'Liver X receptors inhibit proliferation of human colorectal cancer cells and growth of intestinal tumors in mice', Gastroenterology, vol. 144, no. 7. https://doi.org/10.1053/j.gastro.2013.02.005
Lo Sasso, Giuseppe ; Bovenga, Fabiola ; Murzilli, Stefania ; Salvatore, Lorena ; Di Tullio, Giuseppe ; Martelli, Nicola ; D'Orazio, Andria ; Rainaldi, Stefania ; Vacca, Michele ; Mangia, Anita ; Palasciano, Giuseppe ; Moschetta, Antonio. / Liver X receptors inhibit proliferation of human colorectal cancer cells and growth of intestinal tumors in mice. In: Gastroenterology. 2013 ; Vol. 144, No. 7.
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abstract = "Background & Aims: 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. APCmin/+/iVP16LXRα mice also developed fewer, smaller intestinal tumors than APCmin/+/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.",
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AU - Lo Sasso, Giuseppe

AU - Bovenga, Fabiola

AU - Murzilli, Stefania

AU - Salvatore, Lorena

AU - Di Tullio, Giuseppe

AU - Martelli, Nicola

AU - D'Orazio, Andria

AU - Rainaldi, Stefania

AU - Vacca, Michele

AU - Mangia, Anita

AU - Palasciano, Giuseppe

AU - Moschetta, Antonio

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N2 - Background & Aims: 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. APCmin/+/iVP16LXRα mice also developed fewer, smaller intestinal tumors than APCmin/+/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.

AB - Background & Aims: 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. APCmin/+/iVP16LXRα mice also developed fewer, smaller intestinal tumors than APCmin/+/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.

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KW - Mouse Model

KW - NR1H3/NR1H2

KW - Nuclear Receptor

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