FATTY-ACID SYNTHESIS - A POTENTIAL SELECTIVE TARGET FOR ANTINEOPLASTIC THERAPY

OA-519 is a prognostic molecule found in tumor cells from breast cance r patients with markedly worsened prognosis. We purified OA-519 from h uman breast carcinoma cells, obtained its peptide sequence, and unambi guously identified it as fatty acid synthase through sequence homology and enzymology. Tumor fatty acid synthase is an approximate to 270-kD a polypeptide which specifically abolished immunostaining of human bre ast cancers by anti-OA-519 antibodies. Tumor fatty acid synthase oxidi zed NADPH in a malonyl-CoA-dependent fashion and synthesized fatty aci ds composed of 80% palmitate, 10% myristate, and 10% stearate from ace tyl-CoA, malonyl-CoA, and NADPH with a specific activity of 624 nmol o f NADPH oxidized per min per mg. Tumor cell lines with elevated fatty acid synthase showed commensurate increases in incorporation of [U-C-1 4]acetate into acylglycerols demonstrating that fatty acid synthase in creases occur in the context of overall increases in endogenous fatty acid synthesis. Cerulenin inhibited acylglycerol synthesis in tumor ce lls and fibroblast controls in a dose-dependent fashion and also cause d a growth inhibition which generally paralleled the level of endogeno us fatty acid synthesis. Supraphysiologic levels of palmitate, 14 mu M in dimethyl sulfoxide, significantly reversed the growth inhibition c aused by cerulenin at concentrations of up to 5 mu g/ml, indicating th at cerulenin-mediated growth inhibition was due to fatty acid synthase inhibition.