Fatty acid synthase overexpression: target for therapy and reversal of chemoresistance in ovarian cancer

Dirk O. Bauerschlag, Nicolai Maass, Peter Leonhardt, Frederik A. Verburg, Ulrich Pecks, Felix Zeppernick, Agnieszka Morgenroth, Felix M. Mottaghy, Rene Tolba, Ivo Meinhold-Heerlein, Karen Braeutigam*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.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.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.FASN inhibition induced apoptosis in chemosensitive and platinum-resistant ovarian cancer cells and may reverse cisplatin resistance.
Original languageEnglish
JournalJournal of Translational Medicine
Volume13
DOIs
Publication statusPublished - 7 May 2015

Keywords

  • Ovarian cancer
  • FASN
  • FASN inhibitor
  • Cerulenin
  • Biomolecular marker
  • Cisplatin
  • Resistance
  • Chemotherapy
  • F-18-fluoromethylcholine
  • Imaging

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