Interaction between fatty acid synthase- and ErbB-systems in ovarian cancer cells.
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.
Grunt
Thomas W
TW
Signaling Networks Program, Department of Medicine I, Medical University Vienna, Vienna, Austria. thomas.grunt@meduniwien.ac.at
Wagner
Renate
R
Grusch
Michael
M
Berger
Walter
W
Singer
Christian F
CF
Marian
Brigitte
B
Zielinski
Christoph C
CC
Lupu
Ruth
R
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000201:enzymology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*
D015107:4-Butyrolactone; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D054890:Fatty Acid Synthase, Type I; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; C518729:FASN protein, human