FOXO3 Growth Inhibition of Colonic Cells Is Dependent on Intraepithelial Lipid Droplet Density

• Published in: The Journal of biological chemistry 2013-06, Vol.288 (23), p.16274-16281
• Main Authors: Qi, Wentao, Fitchev, Philip S., Cornwell, Mona L., Greenberg, Jordan, Cabe, Maleen, Weber, Christopher R., Roy, Hemant K., Crawford, Susan E., Savkovic, Suzana D.
• Format: Article
• Language: English
• Subjects: Animals; Cancer Biology; Cell Line, Tumor; Cell Proliferation; Colon - metabolism; Colon - pathology; Colon Cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colonic Neoplasms - therapy; Colorectal Cancer; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Epithelial Cells - metabolism; Epithelial Cells - pathology; Forkhead Box Protein O3; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; FOXO3; Gene Expression Regulation, Neoplastic - genetics; Growth; Growth Factors; Humans; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Lipid Droplet; Lipid Metabolism; Lipids; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Mice; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Perilipin-2; Promoter Regions, Genetic; Sirtuins - genetics; Sirtuins - metabolism; Tumor Metabolism; Tumor Suppressor Gene
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.470617

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. Background: The loss of FOXO3 is critical for tumor growth. Results: FOXO3 and lipid droplets (LDs) have feedback regulation, and the loss of FOXO3 leading to increased LDs is key in the growth of colonic cells. Conclusion: FOXO3-dependent LDs provide lipid energy critical for cellular growth. Significance: Identifying regulators of cellular lipid energy could provide new targets for colon cancer treatment.