TY - JOUR
T1 - Interaction between fatty acid synthase- and ErbB-systems in ovarian cancer cells
AU - Grunt, Thomas W.
AU - Wagner, Renate
AU - Grusch, Michael
AU - Berger, Walter
AU - Singer, Christian F.
AU - Marian, Brigitte
AU - Zielinski, Christoph C.
AU - Lupu, Ruth
N1 - Funding Information:
Supported by ‘Medizinisch-Wissenschaftlicher Fonds des Bürgermeisters der Bundeshauptstadt Wien’ #08037 (C.F. Singer, T.W. Grunt), ‘Initiative Krebsforschung’, Medical University Vienna (W. Berger, T.W. Grunt, M. Grusch, B. Marian), and an unrestricted research grant, Hoffmann-La Roche, Basel, Switzerland (T.W. Grunt).
PY - 2009/7/31
Y1 - 2009/7/31
N2 - 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.
AB - 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.
KW - Crosstalk
KW - EGFR
KW - EGFR antibody
KW - ErbB/HER
KW - ErbB2 antibody
KW - ErbB2/HER2
KW - Fatty acid synthase
KW - Ovarian cancer
KW - Receptor tyrosine kinase
KW - Small-molecule tyrosine kinase inhibitor
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U2 - 10.1016/j.bbrc.2009.05.085
DO - 10.1016/j.bbrc.2009.05.085
M3 - Article
C2 - 19467222
AN - SCOPUS:67349136348
SN - 0006-291X
VL - 385
SP - 454
EP - 459
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -