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Acetoacetate inhibits proliferation and ATP production in human cancer lines that overexpress uncoupling protein 2 (UCP2)
Author(s) -
Fine Eugene J,
Miller Anna I,
Sequeira Jeffrey M,
Quadros Edward V,
Feinman Richard D
Publication year - 2008
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.22.2_supplement.598
Subject(s) - glycolysis , cell culture , cell growth , ketone bodies , biology , cancer cell , mitochondrion , biochemistry , atp synthase , oxidative phosphorylation , enzyme , cancer , metabolism , genetics
Dietary carbohydrate restriction provokes increased fatty acid and ketone body availability, effects that plausibly inhibit aggressive glycolytic cancers, particularly if TCA enzymes are preserved but mitochondrial ATP generation is uncoupled, as has been previously reported. Objective: To test the hypothesis that ketone bodies metabolically inhibit cancer cell growth. Methods: We have grown seven aggressive human cancer cell lines, and two control fibroblast lines in vitro in 10 mM glucose (G) vs. glucose plus acetoacetate (G+A}, both 10 mM and have assayed for cell growth, ATP production and UCP2 expression. Comparing G+A vs G there is a strong correlation of cell growth (γ) with ATP production (α) {γ = 0.82α +4; r= 0.98} which applies across all cell lines. Control lines demonstrate normal cell growth and ATP production but no perceptible mitochondrial UCP2 staining, while all cancer lines overexpress UCP2 and demonstrate variable but proportionally inhibited growth and ATP. We conclude that in the lines studied a) there is tight coupling between cell growth and ATP production, supporting metabolic inhibition of glycolysis; b) that UCP2 is overexpressed in the cancer lines but not in the normal fibroblasts. These data provide a plausible mechanism for suppression of mitochondrial ATP production while permitting TCA intermediate‐induced inhibition of glycolytically generated ATP