Cited by 151Cancer, Lipids, and MetabolismLipid metabolism and biosynthesisSphingolipid Metabolism and Signaling

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A Fatty Acid Synthase Blockade Induces Tumor Cell-cycle Arrest by Down-regulating Skp2

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Knowles, Lynn M., Axelrod, Fumiko, Browne, Cecille D., Smith, Jeffrey W.·2004·Journal of Biological Chemistry

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Abstract

In eukaryotes, fatty acid synthase (FAS) is the enzyme responsible for synthesis of palmitate, the precursor of long-chain nonessential fatty acids. FAS is up-regulated in a wide range of cancers and has been suggested as a relevant drug target. Here, two independent approaches are taken toward knocking down FAS and then probing its connection to tumor cell proliferation. In one approach, Orlistat, a drug approved for treating obesity, is used as a potent inhibitor of the thioesterase function of FAS. In a separate strategy, the expression of FAS is suppressed by targeted knock-down with small interfering RNA. In both circumstances, the ablation of FAS activity causes a dramatic down-regulation of Skp2, a component of the E3 ubiquitin ligase that controls the turnover of p27Kip1. These effects ultimately tie into the retinoblastoma protein pathway and lead to a cell-cycle arrest at the G1/S boundary. Altogether, the findings of the study reveal unappreciated links between fatty acid synthase and ubiquitin-dependent proteolysis of cell-cycle regulatory proteins.

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Authors: Knowles, L. M., Axelrod, F., Browne, C. D., & Smith, J. W.
Affiliations: Sanford Burnham Prebys Medical Discovery Institute (US)
Corresponding author: Smith, Jeffrey W.
ORCID: Knowles, Lynn M.
Smith, Jeffrey W.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2004-07
Volume: 279
Issue: 29
Pages: 30540-30545
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m405061200
OpenAlex: W2115307821
Cited by: 146
References: 38
Citations by year: 2026: 3 · 2025: 4 · 2024: 6 · 2023: 5 · 2022: 2 · 2021: 4 · 2019: 4 · 2018: 5 · 2017: 7 · 2016: 4 · 2015: 5 · 2014: 12 · 2013: 6 · 2012: 13
FWCI: 3.48
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 5946 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: National Cancer Institute (CA30199, CA-69306, R01CA069306, CA6982713, P30CA030199)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
Keywords: fatty acid synthase, Skp2, orlistat, cell cycle arrest, G1/S checkpoint, p27, ubiquitin-mediated proteolysis, E3 ubiquitin ligase, tumor cell proliferation, siRNA knockdown, cancer drug targets
MeSH terms: Orlistat, Avidin, Biotin, Cell Cycle, Cell Division, Cell Line, Dose-Response Relationship, Drug, Epithelial Cells, Fatty Acids, Humans, Lactones, Lipase, Obesity, Serine Endopeptidases, Time Factors, Blotting, Western, Down-Regulation, Retinoblastoma Protein, G1 Phase, S Phase, Cell Cycle Proteins, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Palmitic Acid, Tumor Suppressor Proteins, Ubiquitin, RNA, Small Interfering, Ubiquitin-Protein Ligases, S-Phase Kinase-Associated Proteins, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p27, Fatty Acid Synthases

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A Fatty Acid Synthase Blockade Induces Tumor Cell-cycle Arrest by Down-regulating Skp2

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