| First Author | Lo Sasso G | Year | 2013 |
| Journal | Gastroenterology | Volume | 144 |
| Issue | 7 | Pages | 1497-507, 1507.e1-13 |
| PubMed ID | 23419360 | Mgi Jnum | J:316432 |
| Mgi Id | MGI:6837129 | Doi | 10.1053/j.gastro.2013.02.005 |
| Citation | Lo Sasso G, et al. (2013) Liver X receptors inhibit proliferation of human colorectal cancer cells and growth of intestinal tumors in mice. Gastroenterology 144(7):1497-507, 1507.e1-13 |
| abstractText | 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 LXRalpha only in the intestinal epithelium, under the control of villin promoter (iVP16LXRalpha). 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 VP16hLXRalpha, 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 VP16hLXRalpha blocked the G1 phase, increased caspase-dependent apoptosis, and slowed growth of xenograft tumors in mice. iVP16LXRalpha mice formed fewer, smaller tumors than VP16 (control) mice after administration of azoxymethane and dextran sodium sulfate. APC(min/+)/iVP16LXRalpha mice also developed fewer, smaller intestinal tumors than APC(min/+)/iVP16 mice. Gene expression analysis indicated that activation of LXRalpha affected lipid metabolic networks and increased cholesterol efflux in the intestine. CONCLUSIONS: Expression of activated LXRalpha 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. |
