Clinical implications of fatty acid synthase (FAS) in pediatric tumor cell lines

The lipogenic enzyme FAS is markedly elevated in aggressive subsets of certain human cancers. Increased FAS has been implicated both as a poor prognostic indicator and chemotherapeutic target. In an attempt to extend the chemotherapeutic implications to pediatric cancers, we characterized FAS in selected pediatric tumor cell lines [neuroblastoma (SK-N-SH). medulloblastoma (Daoy), malignant rhabdoid tumor of kidney (SM II), and retinoblastoma (Y79)] and then tested the ability of the anti-FAS drug cerulenin to inhibit growth of these lines. Western blotting detected moderate amounts of FAS in SK-N-SH and Y79 and smaller amounts in Daoy and SM II. Relative content was as follows: SK-N-SH > Y79 > > Daoy = SM II. FAS activity also correlated with amount. Dexamethasone (DEX) induced FAS content in SK-H-SH and Daoy hut paradoxically decreased enzyme activity. In contrast, content and activity increased only slightly in DEX-treated SM II and Y79. Nerve growth factor (NGF) had little effect on enzyme content. Deactivation of FAS with cerulenin imparted significant growth inhibition to all tumor cell lines but not to BNL. CL2 hepatocytes. IC₅₀ values were 6.5 μg/ml cerulenin for SM II and 9.5 μg/ml for SK-N-SH and Daoy, which contrasted with BNL. CL2 where the IC₅₀ was >20 μg/ml. Thus, FAS in pediatric tumor lines [1] varied in content and activity among cell lines. [2] exhibited varying degrees of regulation by DEX, and [3] resisted induction by NGF. Inhibition of FAS by cerulenin resulted in significant tumor cell cytotoxicity, thereby implicating FAS a possible chemotherapeutic target in pediatric cancers.