The current study characterizes the lipogenic
enzyme fatty acid synthase (FAS; EC 2.3.1.85) in pediatric tumor cell lines of neural or neural crest origin [
medulloblastoma (Daoy), malignant
rhabdoid tumor of kidney (
SM II),
retinoblastoma (Y79), and
neuroblastoma (SK-N-SH)]. Constitutive FAS content and activity in these lines were compared to human fibroblast cell line Hs27. Hs27 exhibits low levels of FAS and recapitulates
enzyme status in normal human tissues under most physiological conditions. Western analysis detected significantly larger amounts of FAS
protein in Y79 and SK-N-SH than Daoy,
SM II and Hs27. Incorporation of radiolabeled
malonyl-CoA into total cellular
lipid revealed that
enzyme activity correlated with amount. Increased FAS content and activity in Y79 and SK-N-SH relative to the other cell lines and Hs27, in particular, implied enzyme activation in
retinoblastoma and
neuroblastoma lineages. The
enzyme also showed evidence of hormonal regulation, as
dexamethasone induced FAS
protein in Daoy and SK-N-SH. However, hormonal induction of FAS
protein levels did not correlate with activity levels, which led us to speculate phosphorylation as a means of regulating the
enzyme's activity. Finally, the FAS inhibitor
cerulenin was investigated for its ability to suppress
tumor cell growth. After four days of propagation, short-term treatment of cell lines with
drug produced mean IC50s less than 10.5 micrograms/ml (i.e., 5.6 +/- 1.9 for
SM II; 9.3 +/- 1.5 for Daoy; 10.2 +/- 0.2 for SK-N-SH; and 10.4 +/- 2.6 for Y79).
Annexin V assays revealed that
cerulenin initiated apoptosis. The
antineoplastic properties of
cerulenin documented here are consistent with prior studies showing its cytotoxic effects upon other types of
cancer cells and illustrate the potential utility of FAS inhibition as a novel chemotherapeutic approach.