Fatty acid synthase (FAS) is selectively expressed in certain human cancers, including carcinoma of the breast, prostate, colon, ovary, and endometrium, compared to normal human tissues and therefore is a putative tumor marker. In this study, we found FAS concentrations were elevated in cell culture supernatants during cell growth in two human breast cancer cell lines but not other cancer cell lines. A quantitative enzyme-linked immunosorbent assay and Western blot analysis were employed in this study. In addition, serum FAS levels were significantly higher in breast cancer patients with different clinical stages (Stage II: 0.59+/-0.09 units/l, Stage III: 0.79+/-0.13 units/l, and Stage IV: 1.39+/-0.35 units/l) compared with healthy subjects (0.27+/-0.02 units/l, P<0.05). Taken together, our data suggest that FAS expression may be a useful tumor marker for breast cancer and play a role in assessing cancer virulence.
"In 1994 Kuhajda and colleagues reported that a protein (oncogenic antigen-519) linked to poor prognosis in breast cancer was identical to FASN (Kuhajda et al. 1994). Since then FASN has been shown to be up-regulated in a variety of cancers such as breast (Vazquez- Martin et al. 2008; Wang et al. 2001), prostate (Migita et al. 2009) and colon (Notarnicola et al. 2012). The mechanism behind the FASN overexpression is not completely understood but sex steroid hormones and their receptor (Chalbos et al. 1987; Menendez et al. 2005b) as well as the human epidermal growth factor receptor 2 (HER2) (Kumar-Sinha et al. 2003; Vazquez-Martin et al. 2009) have been shown to have an important role involving the mitogen activated protein (MAP) kinase and phosphatidylinositol (PI) 3-kinase signalling cascades (Yang et al. 2002). "
[Show abstract][Hide abstract] ABSTRACT: Background
The lichen compound (+)-protolichesterinic acid (+)-PA, isolated from Iceland moss, has anti-proliferative effects on several cancer cell lines. The chemical structure of (+)-PA is similar to a known fatty acid synthase (FASN) inhibitor C75.
To test whether the anti-proliferative activity of (+)-PA is associated with effects on FASN and HER2 (human epidermal growth factor receptor 2) and major signalling pathways. Synergism between (+)-PA and lapatinib, a HER2 active drug, was also evaluated.
Materials and methods
Pure compound was isolated by preparative high-performance liquid chromatography (HPLC) and purity of (+)-PA analyzed by analytical HPLC. Cell viability was assessed using Crystal violet staining. FASN and HER2 expression was estimated by immunofluorescence. The Meso Scale Discovery (MSD)® assay was used to measure activation of ERK1/2 and AKT. Synergism was estimated by the CalcuSyn software.
Treatment with (+)-PA increased FASN expression in SK-BR-3 cells, which overexpress FASN and HER2, implying a compensatory response to inhibition of FASN activity. HER2 expression was decreased suggesting secondary downregulation. ERK1/2 and AKT signalling pathways were inhibited, probably due to reduced levels of HER2. No effects were observed in T-47D cells. Synergism between (+)-PA and lapatinib was observed in the SK-BR-3 cells.
Results suggest that the primary effect of (+)-PA is inhibition of FASN activity. Synergistic effects with lapatinib were seen only in SK-BR-3 cells, and not T-47D cells, further supporting the notion that (+)-PA acts by inhibiting FASN with secondary effects on HER2 expression and signalling. (+)-PA could therefore be a suitable agent for further testing, alone or in combination treatment against HER2-overexpressing breast cancer.
"Despite being an intracellular protein, it may be released into the extracellular space and may be a biomarker of metabolically demanding human diseases
. Increased FAS levels have been detected in serum of patients with different clinical stages of breast cancer
. Recently, a significant association between circulating levels of FAS and HER2-overexpressing metastatic breast cancer patients has been described
[Show abstract][Hide abstract] ABSTRACT: Background
Lipid metabolism is altered in subjects with liver steatosis. FAS is a key enzyme in de novo lipogenesis and both FAS gene expression and enzymatic activity are primarily regulated by metabolic signals in the liver. Lipoprotein lipase (LPL), the rate-limiting enzyme for the hydrolysis of core triglycerides, plays a pivotal role in lipid metabolism. This study aims to investigate if circulating levels of FAS and LPL could be clinically associated with liver steatosis.
In this work, we present data obtained from a subsample of 94 subjects with liver steatosis enrolled by NUTRIEPA study, a nutritional trial in subjects with liver steatosis. Serum levels of FAS protein and LPL activity were evaluated by ELISA test and by a fluorescent method, respectively. The diagnosis and the degree of liver steatosis were based on laboratory and ecographic measurements. Statistical methods included Kruskal-Wallis analysis of variance and Wilcoxon signed-rank test, where appropriate. The χ2 test has been performed to analyse categorical variables.
The subjects with severe steatosis had significantly higher serum levels of FAS protein and LPL activity compared to subjects with mild and moderate liver steatosis. Moreover, a positive trend in serum levels of FAS expression from lower to higher degree of steatosis was also detected.
We describe a relationship between human liver steatosis and elevated levels of circulating lipogenic enzymes. Increased serum levels of FAS expression and LPL activity could be considered a marker of severe liver steatosis.
Lipids in Health and Disease 10/2012; 11(1):145. DOI:10.1186/1476-511X-11-145 · 2.22 Impact Factor
"Of the respective mRNAs, only three were upregulated by Runx2 (Supplementary Table S6), and among the remaining 13 proteins, 4 of particular interest were subjected to western blot analysis. As shown in Figure 6B, fatty acid synthase (FAS), which is abundantly expressed by PCa cells and serves as a serum marker for cancer progression (48–50), was readily detectable in medium conditioned by Runx2-expressing C4-2B cells, but not in control conditioned medium. Because FAS levels were comparable between the respective cell extracts (Figure 6B), we conclude that Runx2 stimulated FAS secretion. "
[Show abstract][Hide abstract] ABSTRACT: Runx2 is a metastatic transcription factor (TF) increasingly expressed during prostate cancer (PCa) progression. Using PCa cells conditionally expressing Runx2, we previously identified Runx2-regulated genes with known roles in epithelial-mesenchymal transition, invasiveness, angiogenesis, extracellular matrix proteolysis and osteolysis. To map Runx2-occupied regions (R2ORs) in PCa cells, we first analyzed regions predicted to bind Runx2 based on the expression data, and found that recruitment to sites upstream of the KLK2 and CSF2 genes was cyclical over time. Genome-wide ChIP-seq analysis at a time of maximum occupancy at these sites revealed 1603 high-confidence R2ORs, enriched with cognate motifs for RUNX, GATA and ETS TFs. The R2ORs were distributed with little regard to annotated transcription start sites (TSSs), mainly in introns and intergenic regions. Runx2-upregulated genes, however, displayed enrichment for R2ORs within 40 kb of their TSSs. The main annotated functions enriched in 98 Runx2-upregulated genes with nearby R2ORs were related to invasiveness and membrane trafficking/secretion. Indeed, using SDS-PAGE, mass spectrometry and western analyses, we show that Runx2 enhances secretion of several proteins, including fatty acid synthase and metastasis-associated laminins. Thus, combined analysis of Runx2's transcriptome and genomic occupancy in PCa cells lead to defining its novel role in regulating protein secretion.
Nucleic Acids Research 12/2011; 40(8):3538-47. DOI:10.1093/nar/gkr1219 · 9.11 Impact Factor
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