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Lipid droplet accumulation promotes proliferation in colon cells via loss of FOXO3‐dependent cell cycle arrest
Author(s) -
Savkovic Suzana,
Qi Wentao,
Weber Christopher
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1103.9
Subject(s) - foxo3 , cell cycle , cell growth , g1 phase , chemistry , cell cycle checkpoint , flow cytometry , microbiology and biotechnology , cancer research , cell , signal transduction , biology , biochemistry , protein kinase b
Intracellular lipid storing organelles, lipid droplets (LD), are increased in cancer and they are speculated to drive cancer progression. Since the tumor suppressor FOXO3 negatively regulates proliferation, we hypothesize that LD promote cancer progression via loss of FOXO3 activity that leads to increased proliferation. LD accumulation was induced by Oleic Acid (OA) (1mg/ml, 48 h) and inhibited using C75 (fatty acid synthase inhibitor) in colonic cells (HT‐29 and YAMC). FOXO3 activity and the downstream target p27kip1 were examined by western blot, immunofluorescence, and Chip assay. Proliferation and cell cycle distribution were assessed by MTS assay and flow cytometry. OA stimulated and C75 inhibited LD accumulation and proliferation of colonic cells. Overexpression of FOXO3 inhibited proliferation, and was not overcome with OA treatment, suggesting that FOXO3 is downstream of LD in the proliferation cascade. OA treatment significantly decreased total FOXO3 and led to degradation of the cell cycle inhibitor p27kip1 as well as disassociation of FOXO3 from the p27kip1 promoter. In conclusion, LD accumulation promotes proliferation in colon cancer cells by inhibiting FOXO3, which leads to loss of cell cycle arrest and proliferation. We further speculate LD may serve as a pharmacologic target in the development of new cancer therapies.