title: FOXO3 growth inhibition of colonic cells is dependent on intraepithelial lipid droplet density.
abstract: Forkhead transcription factor FOXO3 plays a critical role in suppressing tumor growth, in part, by increasing the cell cycle inhibitor p27kip1, and Foxo3 deficiency in mice results in marked colonic epithelial proliferation. Here, we show in Foxo3-deficient colonic epithelial cells a striking increase in intracytoplasmic lipid droplets (LDs), a dynamic organelle recently observed in human tumor tissue. Although the regulation and function of LDs in non-adipocytes is unclear, we hypothesize that the anti-proliferative effect of FOXO3 was dependent on lowering LD density, thus decreasing fuel energy in both normal and colon cancer cells. In mouse colonic tumors, we found an increased expression of LD coat protein PLIN2 compared with normal colonic epithelial cells. Stimulation of LD density in human colon cancer cells led to a PI3K-dependent loss of FOXO3 and a decrease in the negative regulator of lipid metabolism in Sirtuin6 (SIRT6). Foxo3 deficiency also led to a decrease in SIRT6, revealing the existence of LD and FOXO3 feedback regulation in colonic cells. In parallel, LD-dependent loss of FOXO3 led to its dissociation from the promoter and decreased expression of the cell cycle inhibitor p27kip1. Stimulation of LD density promoted proliferation in colon cancer cells, whereas silencing PLIN2 or overexpression of FOXO3 inhibited proliferation. Taken together, FOXO3 and LDs might serve as new targets for therapeutic intervention of colon cancer.
authors.affiliation: Department of Medicine, Division of Gastroenterology, Northshore University HealthSystem Research Institute, Evanston, Illinois 60201.
authors.forename: Wentao
authors.initials: W
authors.lastname: Qi
authors.affiliation: Department of Pathology, Saint Louis University School of Medicine, St. Louis, Missouri 63104.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Fitchev
authors.affiliation: Department of Pathology, Saint Louis University School of Medicine, St. Louis, Missouri 63104.
authors.forename: Mona L
authors.initials: ML
authors.lastname: Cornwell
authors.affiliation: Department of Medicine, Division of Gastroenterology, Northshore University HealthSystem Research Institute, Evanston, Illinois 60201.
authors.forename: Jordan
authors.initials: J
authors.lastname: Greenberg
authors.affiliation: Department of Medicine, Division of Gastroenterology, Northshore University HealthSystem Research Institute, Evanston, Illinois 60201.
authors.forename: Maleen
authors.initials: M
authors.lastname: Cabe
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois 60637.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Weber
authors.affiliation: Department of Medicine, Division of Gastroenterology, Northshore University HealthSystem Research Institute, Evanston, Illinois 60201.
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Roy
authors.affiliation: Department of Pathology, Saint Louis University School of Medicine, St. Louis, Missouri 63104.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Crawford
authors.affiliation: Department of Medicine, Division of Gastroenterology, Northshore University HealthSystem Research Institute, Evanston, Illinois 60201. Electronic address: SSavkovic@northshore.org.
authors.forename: Suzana D
authors.initials: SD
authors.lastname: Savkovic
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D000070780:Perilipin-2; D011401:Promoter Regions, Genetic; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism
chemical_list: C436291:CDKN1B protein, human; C493961:Cdkn1b protein, mouse; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C000602982:PLIN2 protein, human; D000070780:Perilipin-2; C000602983:Plin2 protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; C501860:Sirt6 protein, mouse; C516592:SIRT6 protein, human; D037761:Sirtuins
keywords: Cancer Biology; Colon Cancer; Colorectal Cancer; FOXO3; Growth; Growth Factors; Lipid Droplet; Lipids; Tumor Metabolism; Tumor Suppressor Gene