title: Fatty acid synthase overexpression: target for therapy and reversal of chemoresistance in ovarian cancer.
abstract: BACKGROUND
  Fatty acid synthase (FASN) is crucial to de novo long-chain fatty acid synthesis, needed to meet cancer cells' increased demands for membrane, energy, and protein production.
  
  
  METHODS
  We investigated FASN overexpression as a therapeutic and chemosensitization target in ovarian cancer tissue, cell lines, and primary cell cultures. FASN expression at mRNA and protein levels was determined by quantitative real-time polymerase chain reaction and immunoblotting and immunohistochemistry, respectively. FASN inhibition's impact on cell viability, apoptosis, and fatty acid metabolism was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide assay, cell death detection enzyme-linked immunosorbent assay, immunoblotting, and (18) F-fluoromethylcholine uptake measurement, respectively.
  
  
  RESULTS
  Relative to that in healthy fallopian tube tissue, tumor tissues had 1.8-fold average FASN protein overexpression; cell lines and primary cultures had 11-fold-100-fold mRNA and protein overexpression. In most samples, the FASN inhibitor cerulenin markedly decreased FASN expression and cell viability and induced apoptosis. Unlike concomitant administration, sequential cerulenin/cisplatin treatment reduced cisplatin's half maximal inhibitory concentration profoundly (up to 54%) in a cisplatin-resistant cell line, suggesting platinum (re)sensitization. Cisplatin-resistant cells displayed lower (18) F-fluoro-methylcholine uptake than did cisplatin-sensitive cells, suggesting that metabolic imaging might help guide therapy.
  
  
  CONCLUSIONS
  FASN inhibition induced apoptosis in chemosensitive and platinum-resistant ovarian cancer cells and may reverse cisplatin resistance.
authors.affiliation: Department of Gynecology and Obstetrics, University Medical Center RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. dbauerschlag@ukaachen.de.
authors.forename: Dirk O
authors.initials: DO
authors.lastname: Bauerschlag
authors.affiliation: Department of Gynecology and Obstetrics, University Medical Center RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. nmaass@ukaachen.de.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Maass
authors.affiliation: Department of Gynecology and Obstetrics, University Medical Center RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. peterleonhardt@freenet.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Leonhardt
authors.affiliation: Department of Nuclear Medicine, University Medical Center RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. fverburg@ukaachen.de.
authors.forename: Frederik A
authors.initials: FA
authors.lastname: Verburg
authors.affiliation: Department of Gynecology and Obstetrics, University Medical Center RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. upecks@ukaachen.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pecks
authors.affiliation: Department of Gynecology and Obstetrics, University Medical Center RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. fzeppernick@ukaachen.de.
authors.forename: Felix
authors.initials: F
authors.lastname: Zeppernick
authors.affiliation: Department of Nuclear Medicine, University Medical Center RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. amorgenroth@ukaachen.de.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Morgenroth
authors.affiliation: Department of Nuclear Medicine, University Medical Center RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. fmottaghy@ukaachen.de.
authors.forename: Felix M
authors.initials: FM
authors.lastname: Mottaghy
authors.affiliation: Institute for Laboratory Animal Science, University Medical Center RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. rtolba@ukaachen.de.
authors.forename: Rene
authors.initials: R
authors.lastname: Tolba
authors.affiliation: Department of Gynecology and Obstetrics, University Medical Center RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. imeinhold@ukaachen.de.
authors.forename: Ivo
authors.initials: I
authors.lastname: Meinhold-Heerlein
authors.affiliation: Department of Gynecology and Obstetrics, University Medical Center RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. kbraeutigam@ukaachen.de.
authors.forename: Karen
authors.initials: K
authors.lastname: Bräutigam
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002569:Cerulenin / Q000378:metabolism; D002794:Choline / Q000031:analogs & derivatives / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D058990:Molecular Targeted Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D019308:Palmitic Acid / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; C516370:fluoromethylcholine; D002569:Cerulenin; D019308:Palmitic Acid; D064429:Fatty Acid Synthases; D002794:Choline