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Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287 [E. S. P., J. A. D., W. F. H.], and Clinical Immunology Section, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224 [F. J. C.]
Pharmacological inhibitors of the anabolic enzyme, fatty acid synthase (FAS), including the natural product cerulenin and the novel compound c75, are selectively cytotoxic to cancer cells via induction of apoptosis, apparently related to the tumor cell phenotype of abnormally elevated fatty acid synthetic metabolism. As part of a larger effort to understand the immediate downstream effect of FAS inhibition that leads to apoptosis, the effects of these inhibitors on cell cycle progression were examined. Both FAS inhibitors produce rapid, profound inhibition of DNA replication and S phase progression in human cancer cells. The dose responses for fatty acid synthesis inhibition and DNA synthesis inhibition are similar. The kinetics of both effects are rapid, with fatty acid synthesis inhibition occurring within 30 min and DNA synthesis inhibition occurring within 90 min of drug exposure. Meanwhile, apoptotic changes are not detected until 6 h or later after inhibitor exposure. Fatty acid synthetic pathway activity and the magnitude of DNA synthesis inhibition by FAS inhibitors are increased in parallel by withdrawal of lipid-containing serum from the cultures. The mechanism of DNA synthesis inhibition by cerulenin is indirect, because expression of certain viral oncogenes rescues DNA synthesis/S phase progression in cerulenin-exposed cells. The data suggest a direct linkage at a regulatory level, between fatty acid synthesis and DNA synthesis in proliferating tumor cells.
1 This work was supported by R29CA75219. E. S. P. is supported by a Passano Clinician Scientist Award, awarded through the Johns Hopkins University School of Medicine.
2 To whom requests for reprints should be addressed, at Department of Pathology, AA154C, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, Baltimore, MD 21224. Phone: (410) 550-3670; Fax: (410) 550-0075; E-mail: epizer@jhmi.edu.
Received 7/ 7/98. Accepted 9/ 1/98.
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