A fatty acid synthase blockade induces tumor cell-cycle arrest by down-regulating Skp2.
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.
Knowles
Lynn M
LM
Cancer Research Center, The Burnham Institute, La Jolla, California 92037, USA.
Axelrod
Fumiko
F
Browne
Cecille D
CD
Smith
Jeffrey W
JW
D001360:Avidin / Q000378:metabolism; D001710:Biotin / Q000737:chemistry; D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D016193:G1 Phase; D006801:Humans; D007783:Lactones / Q000378:metabolism / Q000494:pharmacology*; D008049:Lipase / Q000037:antagonists & inhibitors; D009765:Obesity / Q000188:drug therapy; D000077403:Orlistat; D019308:Palmitic Acid / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000737:chemistry; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D018797:Cell Cycle Proteins; D005227:Fatty Acids; D007783:Lactones; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D001360:Avidin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019308:Palmitic Acid; D001710:Biotin; D000077403:Orlistat; D064429:Fatty Acid Synthases; D044767:Ubiquitin-Protein Ligases; D008049:Lipase; D012697:Serine Endopeptidases