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Fatty Acid Synthase (FAS): A Target for Cytotoxic Antimetabolites in HL60 Promyelocytic Leukemia Cells¹

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287

Many human cancers express elevated levels of fatty acid synthase (FAS), with correspondingly increased fatty acid synthesis and abnormal fatty acid utilization. Recent studies have shown that the FAS inhibitor, cerulenin, is selectively cytotoxic to cell lines derived from human malignancies, suggesting that those carcinoma cells are dependent upon endogenous fatty acid synthesis for growth. These data further suggest that the fatty acid synthesis pathway is a potential target for chemotherapy development. The present studies demonstrate that cerulenin cytotoxicity is mediated by fatty acid pathway inhibition. Proliferating HL60 promyelocytic leukemia cells express high levels of FAS mRNA and protein and synthesize fatty acid predominantly for membrane phospholipid. Following exposure to 12-O-tetradecanoylphorbol-13-acetate, the FAS expression in HL60 cells is abolished, fatty acid synthesis diminishes, and the cells become insensitive to cerulenin while acquiring a differentiated, macrophage-like phenotype. HL60 cells adapted to growth in serum- and fatty acid-free medium show a dose-dependent sensitivity to cerulenin, which is reversed by palmitate, the major product of FAS, indicating that cerulenin cytotoxicity is mediated through fatty acid starvation. Cells grown in the presence of exogenous fatty acid partially downmodulate FAS expression and increase mean cell volume (phospholipid mass/cell) but retain their sensitivity to cerulenin, which is reversed by 3-fold excess oleate supplementation. These results demonstrate that malignant cells can retain dependence on endogenous fatty acid synthesis and sensitivity to FAS inhibitors in the presence of physiological fatty acid levels and thus support the notion that FAS inhibitors may be useful in treating cancer in vivo.

¹ Supported by a grant from the American Institute of Cancer Research, the W. W. Smith Charitable Trust, and a grant from the Susan G. Komen Foundation. E. P. was partially supported by NIH Grant T32 AI 07247. The abstract was presented at the 1994 AACR Annual Meeting.

² To whom requests for reprints should be addressed, at Department of Pathology, Johns Hopkins Medical Institutions, 720 Rutland Avenue, Ross 512, Baltimore, MD 21205. Phone: (410) 955-5014; Fax: (410) 550-5158; E-mail: fkuhajda@welchlink.welch.jhu.edu.

Received 7/19/95. Accepted 12/ 8/95.

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