FATTY-ACID SYNTHESIS - A POTENTIAL SELECTIVE TARGET FOR ANTINEOPLASTIC THERAPY
FATTY-ACID SYNTHESIS - A POTENTIAL SELECTIVE TARGET FOR ANTINEOPLASTIC THERAPY
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DOI：
10.1073/pnas.91.14.6379
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发表时间：
1994-07-05
影响因子：
11.1
通讯作者：
PASTERNACK, GR
中科院分区：
文献类型：
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作者：
KUHAJDA, FP;JENNER, K;PASTERNACK, GR
OA-519是在来自具有显著恶化的预后的乳腺癌患者的肿瘤细胞中发现的预后分子。我们从人乳腺癌细胞中纯化了OA-519，获得了它的肽序列，并通过序列同源性和酶学性质明确鉴定它为脂肪酸合酶。肿瘤脂肪酸合成酶是一种分子量约为270 kDa的多肽，它特异性地消除了抗OA-519抗体对人乳腺癌的免疫染色。肿瘤脂肪酸合成酶以丙二酰辅酶A依赖性方式氧化NADPH，并从乙酰辅酶A、丙二酰辅酶A和NADPH合成由80%棕榈酸酯、10%肉豆蔻酸酯和10%硬脂酸酯组成的脂肪酸，比活性为624 nmol NADPH氧化/min/mg。脂肪酸合成酶升高的肿瘤细胞系显示[U-C-14]乙酸酯掺入酰基甘油的相应增加，表明脂肪酸合成酶增加发生在内源性脂肪酸合成总体增加的背景下。浅蓝菌素以剂量依赖性方式抑制肿瘤细胞和成纤维细胞对照中的酰基甘油合成，并且还引起生长抑制，其通常抑制内源性脂肪酸合成水平。超生理水平的棕榈酸酯，14 μ M的二甲基亚砜，显着逆转浅蓝菌素浓度高达5 μ g/ml，表明浅蓝菌素介导的生长抑制是由于脂肪酸合成酶抑制引起的生长抑制。
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 approximate to 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-C-14]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 mu M in dimethyl sulfoxide, significantly reversed the growth inhibition caused by cerulenin at concentrations of up to 5 mu g/ml, indicating that cerulenin-mediated growth inhibition was due to fatty acid synthase inhibition.