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 Li, J.-N. Articles by Pizer, E. S. Search for Related Content PubMed PubMed Citation Articles by Li, J.-N. Articles by Pizer, E. S.

Pharmacological Inhibition of Fatty Acid Synthase Activity Produces Both Cytostatic and Cytotoxic Effects Modulated by p53¹

Department of Pathology, Johns Hopkins Medical Institutions [J-N. L., W. F. H., E. S. P.], and Laboratory of Biological Chemistry [M. G.], Research Resources Branch/Flow Cytometry Unit [F. J. C.], and Laboratory of Molecular Genetics [T. S. K., M. K. E.], Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224

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 G₂ 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 G₁ and G₂. 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.

This article has been cited by other articles:

				J. Ross, A. M. Najjar, M. Sankaranarayanapillai, W. P. Tong, K. Kaluarachchi, and S. M. Ronen Fatty acid synthase inhibition results in a magnetic resonance-detectable drop in phosphocholine Mol. Cancer Ther., August 1, 2008; 7(8): 2556 - 2565. [Abstract] [Full Text] [PDF]

				R. Xiao, Y. Su, R. C. M. Simmen, and F. A. Simmen Dietary soy protein inhibits DNA damage and cell survival of colon epithelial cells through attenuated expression of fatty acid synthase Am J Physiol Gastrointest Liver Physiol, April 1, 2008; 294(4): G868 - G876. [Abstract] [Full Text] [PDF]

				A. Beckers, S. Organe, L. Timmermans, K. Scheys, A. Peeters, K. Brusselmans, G. Verhoeven, and J. V. Swinnen Chemical Inhibition of Acetyl-CoA Carboxylase Induces Growth Arrest and Cytotoxicity Selectively in Cancer Cells Cancer Res., September 1, 2007; 67(17): 8180 - 8187. [Abstract] [Full Text] [PDF]

				W. Zhou, W. F. Han, L. E. Landree, J. N. Thupari, M. L. Pinn, T. Bililign, E. K. Kim, A. Vadlamudi, S. M. Medghalchi, R. El Meskini, et al. Fatty Acid Synthase Inhibition Activates AMP-Activated Protein Kinase in SKOV3 Human Ovarian Cancer Cells Cancer Res., April 1, 2007; 67(7): 2964 - 2971. [Abstract] [Full Text] [PDF]

				C. D. Browne, E. J. Hindmarsh, and J. W. Smith Inhibition of endothelial cell proliferation and angiogenesis by orlistat, a fatty acid synthase inhibitor FASEB J, October 1, 2006; 20(12): 2027 - 2035. [Abstract] [Full Text] [PDF]

				F. P. Kuhajda Fatty Acid synthase and cancer: new application of an old pathway. Cancer Res., June 15, 2006; 66(12): 5977 - 5980. [Abstract] [Full Text] [PDF]

				V. Chajes, M. Cambot, K. Moreau, G. M. Lenoir, and V. Joulin Acetyl-CoA Carboxylase {alpha} Is Essential to Breast Cancer Cell Survival. Cancer Res., May 15, 2006; 66(10): 5287 - 5294. [Abstract] [Full Text] [PDF]

				L. Carlisle-Moore, C. R. Gordon, C. A. Machutta, W. T. Miller, and P. J. Tonge Substrate Recognition by the Human Fatty-acid Synthase J. Biol. Chem., December 30, 2005; 280(52): 42612 - 42618. [Abstract] [Full Text] [PDF]

				K. Brusselmans, E. De Schrijver, G. Verhoeven, and J. V. Swinnen RNA Interference-Mediated Silencing of the Acetyl-CoA-Carboxylase-{alpha} Gene Induces Growth Inhibition and Apoptosis of Prostate Cancer Cells Cancer Res., August 1, 2005; 65(15): 6719 - 6725. [Abstract] [Full Text] [PDF]

				J. A. Menendez, L. Vellon, and R. Lupu Antitumoral actions of the anti-obesity drug orlistat (XenicalTM) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene Ann. Onc., August 1, 2005; 16(8): 1253 - 1267. [Abstract] [Full Text] [PDF]

				L. M. Knowles, F. Axelrod, C. D. Browne, and J. W. Smith A Fatty Acid Synthase Blockade Induces Tumor Cell-cycle Arrest by Down-regulating Skp2 J. Biol. Chem., July 16, 2004; 279(29): 30540 - 30545. [Abstract] [Full Text] [PDF]

				A. Vecchini, V. Ceccarelli, F. Susta, P. Caligiana, P. Orvietani, L. Binaglia, G. Nocentini, C. Riccardi, G. Calviello, P. Palozza, et al. Dietary {alpha}-linolenic acid reduces COX-2 expression and induces apoptosis of hepatoma cells J. Lipid Res., February 1, 2004; 45(2): 308 - 316. [Abstract] [Full Text] [PDF]

				W. Zhou, P. J. Simpson, J. M. McFadden, C. A. Townsend, S. M. Medghalchi, A. Vadlamudi, M. L. Pinn, G. V. Ronnett, and F. P. Kuhajda Fatty Acid Synthase Inhibition Triggers Apoptosis during S Phase in Human Cancer Cells Cancer Res., November 1, 2003; 63(21): 7330 - 7337. [Abstract] [Full Text] [PDF]

				S. Rossi, E. Graner, P. Febbo, L. Weinstein, N. Bhattacharya, T. Onody, G. Bubley, S. Balk, and M. Loda Fatty Acid Synthase Expression Defines Distinct Molecular Signatures in Prostate Cancer Mol. Cancer Res., August 1, 2003; 1(10): 707 - 715. [Abstract] [Full Text] [PDF]

				E. De Schrijver, K. Brusselmans, W. Heyns, G. Verhoeven, and J. V. Swinnen RNA Interference-mediated Silencing of the Fatty Acid Synthase Gene Attenuates Growth and Induces Morphological Changes and Apoptosis of LNCaP Prostate Cancer Cells Cancer Res., July 1, 2003; 63(13): 3799 - 3804. [Abstract] [Full Text] [PDF]

				F. D. Camassei, R. Cozza, A. Acquaviva, A. Jenkner, L. Rava, R. Gareri, A. Donfrancesco, C. Bosman, P. Vadala, T. Hadjistilianou, et al. Expression of the Lipogenic Enzyme Fatty Acid Synthase (FAS) in Retinoblastoma and Its Correlation with Tumor Aggressiveness Invest. Ophthalmol. Vis. Sci., June 1, 2003; 44(6): 2399 - 2403. [Abstract] [Full Text] [PDF]

				C. Kumar-Sinha, K. W. Ignatoski, M. E. Lippman, S. P. Ethier, and A. M. Chinnaiyan Transcriptome Analysis of HER2 Reveals a Molecular Connection to Fatty Acid Synthesis Cancer Res., January 1, 2003; 63(1): 132 - 139. [Abstract] [Full Text] [PDF]

				T. Van de Sande, E. De Schrijver, W. Heyns, G. Verhoeven, and J. V. Swinnen Role of the Phosphatidylinositol 3'-Kinase/PTEN/Akt Kinase Pathway in the Overexpression of Fatty Acid Synthase in LNCaP Prostate Cancer Cells Cancer Res., February 1, 2002; 62(3): 642 - 646. [Abstract] [Full Text] [PDF]