This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhou, W. Articles by Kuhajda, F. P. Search for Related Content PubMed PubMed Citation Articles by Zhou, W. Articles by Kuhajda, F. P.

Fatty Acid Synthase Inhibition Activates AMP-Activated Protein Kinase in SKOV3 Human Ovarian Cancer Cells

Departments of ¹ Pathology, ² Neuroscience, ³ Neurology, ⁴ Oncology, and ⁵ Biological Chemistry, The Johns Hopkins University School of Medicine; ⁶ Department of Chemistry, The Johns Hopkins University; and ⁷ FASgen, Inc., Baltimore, Maryland

Requests for reprints: Francis P. Kuhajda, Department of Pathology, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, Baltimore, MD 21224. Phone: 410-550-0671; Fax: 410-550-0075; E-mail: fkuhajda{at}jhmi.edu.

Fatty acid synthase (FAS), the enzyme responsible for the de novo synthesis of fatty acids, is highly expressed in ovarian cancers and most common human carcinomas. Inhibition of FAS and activation of AMP-activated protein kinase (AMPK) have been shown to be cytotoxic to human cancer cells in vitro and in vivo. In this report, we explore the cytotoxic mechanism of action of FAS inhibition and show that C93, a synthetic FAS inhibitor, increases the AMP/ATP ratio, activating AMPK in SKOV3 human ovarian cancer cells, which leads to cytotoxicity. As a physiologic consequence of AMPK activation, acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of fatty acid synthesis, was phosphorylated and inhibited whereas glucose oxidation was increased. Despite these attempts to conserve energy, the AMP/ATP ratio increased with worsening cellular redox status. Pretreatment of SKOV3 cells with compound C, an AMPK inhibitor, substantially rescued the cells from C93 cytotoxicity, indicating its dependence on AMPK activation. 5-(Tetradecyloxy)-2-furoic acid, an ACC inhibitor, did not activate AMPK despite inhibiting fatty acid synthesis pathway activity and was not significantly cytotoxic to SKOV3 cells. This indicates that substrate accumulation from FAS inhibition triggering AMPK activation, not end-product depletion of fatty acids, is likely responsible for AMPK activation. C93 also exhibited significant antitumor activity and apoptosis against SKOV3 xenografts in athymic mice without significant weight loss or cytotoxicity to proliferating cellular compartments such as bone marrow, gastrointestinal tract, or skin. Thus, pharmacologic FAS inhibition selectively activates AMPK in ovarian cancer cells, inducing cytotoxicity while sparing most normal human tissues from the pleiotropic effects of AMPK activation. [Cancer Res 2007;67(7):2964–71]

This article has been cited by other articles:

				J. R. Fay, V. Steele, and J. A. Crowell Energy Homeostasis and Cancer Prevention: The AMP-Activated Protein Kinase Cancer Prevention Research, April 1, 2009; 2(4): 301 - 309. [Abstract] [Full Text] [PDF]

				J. L. Little, F. B. Wheeler, C. Koumenis, and S. J. Kridel Disruption of crosstalk between the fatty acid synthesis and proteasome pathways enhances unfolded protein response signaling and cell death Mol. Cancer Ther., December 1, 2008; 7(12): 3816 - 3824. [Abstract] [Full Text] [PDF]

				C. Plathow and W. A. Weber Tumor Cell Metabolism Imaging J. Nucl. Med., June 1, 2008; 49(Suppl_2): 43S - 63S. [Abstract] [Full Text] [PDF]

				H. Orita, J. Coulter, E. Tully, F. P. Kuhajda, and E. Gabrielson Inhibiting Fatty Acid Synthase for Chemoprevention of Chemically Induced Lung Tumors Clin. Cancer Res., April 15, 2008; 14(8): 2458 - 2464. [Abstract] [Full Text] [PDF]

				S. R. Bloom, F. P. Kuhajda, I. Laher, X. Pi-Sunyer, G. V. Ronnett, T. M.M. Tan, and D. S. Weigle The Obesity Epidemic: Pharmacological Challenges Mol. Interv., April 1, 2008; 8(2): 82 - 98. [Abstract] [Full Text] [PDF]

				H. Orita, J. Coulter, C. Lemmon, E. Tully, A. Vadlamudi, S. M. Medghalchi, F. P. Kuhajda, and E. Gabrielson Selective Inhibition of Fatty Acid Synthase for Lung Cancer Treatment Clin. Cancer Res., December 1, 2007; 13(23): 7139 - 7145. [Abstract] [Full Text] [PDF]