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

被引：97

作者：

Grunt, Thomas W. ^{[1
,2
,3
]}

Wagner, Renate ^{[1
,2
]}

Grusch, Michael ^{[4
]}

Berger, Walter ^{[4
]}

Singer, Christian F. ^{[5
]}

Marian, Brigitte ^{[4
]}

Zielinski, Christoph C. ^{[1
,3
]}

Lupu, Ruth ^{[6
]}

机构：

[1] Med Univ Vienna, Div Oncol, Dept Med 1, A-1090 Vienna, Austria

[2] Med Univ Vienna, Signaling Networks Program, Dept Med 1, A-1090 Vienna, Austria

[3] Ludwig Boltzmann Cluster Oncol, Vienna, Austria

[4] Med Univ Vienna, Inst Canc Res, Dept Med 1, A-1090 Vienna, Austria

[5] Med Univ Vienna, Div Special Gynecol, Dept Obstet Gynecol, A-1090 Vienna, Austria

[6] Mayo Canc Ctr, Mayo Clin, Div Expt Pathol, Rochester, MN USA

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2009年 / 385卷 / 03期

关键词：

Crosstalk; EGFR; EGFR antibody; ErbB/HER; ErbB2/HER2; ErbB2; antibody; Fatty acid synthase; Ovarian cancer; Receptor tyrosine kinase; Small-molecule tyrosine kinase inhibitor; PROTEIN EXPRESSION; BREAST-CANCER; SIGNALING PATHWAY; GENE PROMOTER; RECEPTOR GENE; ACTIVATION; OVEREXPRESSION; CARCINOMA; KINASE; SP1;

D O I：

10.1016/j.bbrc.2009.05.085

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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, EGER, 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 down regulation. Taken together, interference with FASN and ErbB abrogates their oncogenicity and should be exploited for ovarian cancer treatment.,(c) 2009 Elsevier Inc. All rights reserved.

引用

页码：454 / 459

页数：6

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