Fatty acid synthesis: a potential selective target for antineoplastic therapy.
OA-519 is a prognostic molecule found in tumor cells from breast cancer patients with markedly worsened prognosis. We purified OA-519 from human breast carcinoma cells, obtained its peptide sequence, and unambiguously identified it as fatty acid synthase through sequence homology and enzymology. Tumor fatty acid synthase is an approximately 270-kDa polypeptide which specifically abolished immunostaining of human breast cancers by anti-OA-519 antibodies. Tumor fatty acid synthase oxidized NADPH in a malonyl-CoA-dependent fashion and synthesized fatty acids composed of 80% palmitate, 10% myristate, and 10% stearate from acetyl-CoA, malonyl-CoA, and NADPH with a specific activity of 624 nmol of NADPH oxidized per min per mg. Tumor cell lines with elevated fatty acid synthase showed commensurate increases in incorporation of [U-14C]acetate into acylglycerols demonstrating that fatty acid synthase increases occur in the context of overall increases in endogenous fatty acid synthesis. Cerulenin inhibited acylglycerol synthesis in tumor cells and fibroblast controls in a dose-dependent fashion and also caused a growth inhibition which generally paralleled the level of endogenous fatty acid synthesis. Supraphysiologic levels of palmitate, 14 microM in dimethyl sulfoxide, significantly reversed the growth inhibition caused by cerulenin at concentrations of up to 5 micrograms/ml, indicating that cerulenin-mediated growth inhibition was due to fatty acid synthase inhibition.
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21205.
F P
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Kuhajda
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K
Jenner
F D
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Wood
R A
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Hennigar
L B
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Jacobs
J D
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Dick
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Pasternack
D000085:Acetates / Q000378:metabolism; D000906:Antibodies; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor / Q000032:analysis*; D001798:Blood Proteins / Q000032:analysis / Q000302:isolation & purification* / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D002250:Carbon Radioisotopes; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002569:Cerulenin / Q000633:toxicity; D015195:Drug Design; D064429:Fatty Acid Synthases / Q000032:analysis / Q000302:isolation & purification* / Q000378:metabolism*; D005227:Fatty Acids / Q000096:biosynthesis*; D005260:Female; D006242:Haptoglobins; D006801:Humans; D007150:Immunohistochemistry; D007700:Kinetics; D008316:Malonyl Coenzyme A; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000633:toxicity*; D011379:Prognosis; D014407:Tumor Cells, Cultured
D000085:Acetates; D000906:Antibodies; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D001798:Blood Proteins; D002250:Carbon Radioisotopes; D005227:Fatty Acids; C058632:HPR protein, human; D006242:Haptoglobins; D010169:Palmitic Acids; D002569:Cerulenin; D019308:Palmitic Acid; D008316:Malonyl Coenzyme A; D064429:Fatty Acid Synthases