Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells.
Fatty acid synthase (FAS) activity is a potential therapeutic target to treat cancer and obesity. Here, we have identified a molecular link between FAS and HER2 (erbB-2) oncogene, a marker for poor prognosis that is overexpressed in 30% of breast and ovarian cancers. Pharmacological FAS inhibitors cerulenin and C75 were found to suppress p185(HER2) oncoprotein expression and tyrosine-kinase activity in breast and ovarian HER2 overexpressors. Similarly, p185(HER2) expression was dramatically down-regulated when FAS gene expression was silenced by using the highly sequence-specific mechanism of RNA interference (RNAi). Pharmacological and RNAi-mediated silencing of FAS specifically down-regulated HER2 mRNA and, concomitantly, caused a prominent up-regulation of PEA3, a transcriptional repressor of HER2. A cytoplasmic redistribution of p185(HER2) was associated with marked morphological changes of FAS RNAi-transfected cells, whereas chemical inhibitors of FAS promoted a striking nuclear accumulation of p185(HER2). The simultaneous targeting of FAS and HER2 by chemical FAS inhibitors and the humanized antibody directed against p185(HER2) trastuzumab, respectively, was synergistically cytotoxic toward HER2 overexpressors. Similarly, concurrent RNAi-mediated silencing of FAS and HER2 genes synergistically stimulated apoptotic cell death in HER2 overexpressors. p185(HER2) was synergistically down-regulated after simultaneous inhibition of FAS and HER2 by either pharmacological inhibitors or small interfering RNA. These findings provide evidence of an active role of FAS in cancer evolution by specifically regulating oncogenic proteins closely related to malignant transformation, strongly suggesting that HER2 oncogene may act as the key molecular sensor of energy imbalance after the perturbation of tumor-associated FAS hyperactivity in cancer cells.
Menendez
Javier A
JA
Department of Medicine, Evanston Northwestern Healthcare, 1001 University Place, Evanston, IL 60201, USA.
Vellon
Luciano
L
Mehmi
Inderjit
I
Oza
Bharvi P
BP
Ropero
Santiago
S
Colomer
Ramon
R
Lupu
Ruth
R
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized; D000935:Antifungal Agents / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism; D017209:Apoptosis; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D048429:Cell Size; D002470:Cell Survival; D002569:Cerulenin / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000068878:Trastuzumab
D015107:4-Butyrolactone; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000935:Antifungal Agents; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002569:Cerulenin; D064429:Fatty Acid Synthases; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; D000068878:Trastuzumab; C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; C065788:transcription factor PEA3