Pharmacological Inhibition of Fatty Acid Synthase Activity Produces Both Cytostatic and Cytotoxic Effects Modulated by p53
2001
Fatty acid synthetic metabolism is abnormally elevated in tumor cells,
and pharmacological inhibitors of the anabolic enzyme fatty acid
synthase (FAS), including the natural product cerulenin and the novel
synthetic compound c75, are selective inhibitors of tumor cell growth.
We have recently reported that these two FAS inhibitors both produce
rapid, potent inhibition of DNA replication and S-phase progression in
human cancer cells, as well as apoptotic death. Here we report an
additional characterization of the cellular response to FAS inhibition.
RKO colon carcinoma cells were selected for study because they undergo
little apoptosis within the first 24 h after FAS inhibition.
Instead, RKO cells exhibited a biphasic stress response with a
transient accumulation in S and G 2 at 4 and 8 h that
corresponds to a marked reduction in cyclin A- and B1-associated kinase
activities, and then by accumulation of p53 and p21 proteins at 16 and
24 h and growth arrest in G 1 and G 2 . The
response of RKO cells to FAS inhibition resembled a genotoxic stress
response, but DNA damage did not appear to be an important downstream
effect of FAS inhibition, because none was detected using the single
cell gel electrophoresis assay (comet assay) to assess DNA damage. p53
function is probably important in protecting RKO cells from FAS
inhibition because, similar to many other tumor lines, RKO cells
expressing a dominant negative mutant p53 gene underwent
extensive apoptosis within 24 h after FAS inhibition.
Sensitization of cells to FAS inhibitors by the loss of p53 raises the
possibility that these agents may be clinically useful against
malignancies carrying p53 mutations. Whereas induction of apoptosis
appeared related to accumulation of the substrate, malonyl-CoA, after
FAS inhibition, the cytostatic effects were independent of malonyl-CoA
accumulation and may have resulted from product depletion.
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