Interaction between fatty acid synthase- and ErbB-systems in ovarian cancer cells

Thomas W. Grunt, Renate Wagner, Michael Grusch, Walter Berger, Christian F. Singer, Brigitte Marian, Christoph C. Zielinski, Ruth Lupu

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Fatty acid synthase (FASN) represents a metabolic oncogene. It produces phospholipids for membrane microdomains that accommodate receptor tyrosine kinases including Epidermal Growth Factor-Receptor (EGFR, ErbB1) and ErbB2 (HER2/neu). FASN and ErbBs are overexpressed in ovarian cancer. We examined the effect of FASN and ErbB inhibition on A2780 and SKOV3 ovarian cancer cells. Growth assays reveal that FASN inhibitor C75 sensitizes tumor cells against anti-ErbB drugs (pelitinib [EKB-569], canertinib [CI-1033], erlotinib, cetuximab, matuzumab, trastuzumab) suggesting FASN/ErbB cooperation. qRT-PCR and Western blotting revealed that C75 represses FASN, EGFR, ErbB2, and AKT suggesting that FASN-induced membrane microdomains accommodate/stabilize ErbBs and facilitate AKT recruitment/activation. Our data indicate that AKT is crucial for ErbB/FASN interaction, AKT cross-inhibits ERK and feeds loops that boost FASN and EGFR transcription, and EGFR and ErbB2 must be co-silenced for maximal FASN downregulation. Taken together, interference with FASN and ErbB abrogates their oncogenicity and should be exploited for ovarian cancer treatment.

Original languageEnglish (US)
Pages (from-to)454-459
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume385
Issue number3
DOIs
StatePublished - Jul 31 2009

Keywords

  • Crosstalk
  • EGFR
  • EGFR antibody
  • ErbB/HER
  • ErbB2 antibody
  • ErbB2/HER2
  • Fatty acid synthase
  • Ovarian cancer
  • Receptor tyrosine kinase
  • Small-molecule tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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