Molecular Pathways: Fatty Acid Synthase

Jones, Suzanne F.; Infante, Jeffrey R.

doi:10.1158/1078-0432.ccr-15-0126

Cited by 216 publications

(193 citation statements)

References 43 publications

Supporting

Mentioning

187

Contrasting

Unclassified

Order By: Relevance

“…21 As a major enzyme in lipogenesis, FASN has been the main target for developing small molecule inhibitors. 46,47 Virtually all these small molecules inhibit b-ketoacyle-reductase, which is critical for FASN's enzymatic activity. A complete list of FASN inhibitors can be found in a recent review.…”

Section: Fasn Is Required For Akt and Akt/c-met Driven Hepatocarcinogmentioning

confidence: 99%

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

et al. 2017

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC), the most frequent primary tumor of the liver, is an aggressive cancer type with limited treatment options. Cumulating evidence underlines a crucial role of aberrant lipid biosynthesis (a process known as de novo lipogenesis) along carcinogenesis. Previous studies showed that suppression of fatty acid synthase (FASN), the major enzyme responsible for de novo lipogenesis, is highly detrimental for the in vitro growth of HCC cell lines. To assess whether de novo lipogenesis is required for liver carcinogenesis, we have generated various mouse models of liver cancer by stably overexpressing candidate oncogenes in the mouse liver via hydrodynamic gene delivery. We found that overexpression of FASN in the mouse liver is unable to malignantly transform hepatocytes. However, genetic deletion of FASN totally suppresses hepatocarcinogenesis driven by AKT and AKT/c-Met protooncogenes in mice. On the other hand, liver tumor development is completely unaffected by FASN depletion in mice coexpressing b-catenin and c-Met. Our data indicate that tumors might be either addicted to or independent from de novo lipogenesis for their growth depending on the oncogenes involved. Additional investigation is required to unravel the molecular mechanisms whereby some oncogenes render cancer cells resistant to inhibition of de novo lipogenesis.

show abstract

Section: Fasn Is Required For Akt and Akt/c-met Driven Hepatocarcinogmentioning

confidence: 99%

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

et al. 2017

View full text Add to dashboard Cite

show abstract

“…In cancer, however, cells overexpress FASN enzyme to synthesize almost all their fatty acids de novo (14,16). We and others have shown that blocking FASN activity has anticancer activity via the apoptotic pathway in vitro and in vivo (17)(18)(19), by disrupting lipid membrane synthesis and modification of protein palmitoylation and deregulating oncogenic signaling pathways (20,21).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation of Fatty Acid Synthase and EGFR Inhibition in Triple-Negative Breast Cancer

Giró-Perafita

Palomeras

Lum

et al. 2016

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Triple-negative breast cancer (TNBC) lacks an approved targeted therapy. Despite initial good response to chemotherapy, 30% of the patients relapse within 5 years after treatment. EGFR overexpression is a common marker in TNBC, and its expression has been correlated with poor outcome. Inhibition of fatty acid synthase (FASN) activity leads to apoptosis of human carcinoma cells overexpressing FASN. We tested the hypothesis that blocking FASN in combination with anti-EGFR signaling agents would be an effective antitumor strategy in sensitive and chemoresistant TNBC.Experimental Design: Several TNBC cell lines and 29 primary tumors were included to determine whether FASN is a potential target in TNBC. Doxorubicin-resistant TNBC cell lines (231DXR and HCCDXR) have been developed and characterized in our laboratory. Cellular and molecular interactions of anti-FASN compounds (EGCG and C75) with cetuximab were analyzed. In vivo tumor growth inhibition was evaluated after cetuximab, EGCG, or the combination in TNBC orthoxenograft models.Results: TNBC cell lines showed overexpression of FASN enzyme and its inhibition correlated to FASN levels. FASN staining was observed in all of the 29 TNBC tumor samples. In vitro, EGCG and C75 plus cetuximab showed strong synergism in sensitive and chemoresistant cells. In vivo, the combination of EGCG with cetuximab displayed strong antitumor activity against the sensitive and chemoresistant TNBC orthoxenografts, without signs of toxicity.Conclusions: Our results show that the simultaneous blockade of FASN and EGFR is effective in preclinical models of sensitive and chemoresistant TNBC.

show abstract

“…Tumour cells present a typical phenotype of abnormally elevated fatty acid synthase (FAS) activity, which indicates that this enzyme is a good target for treating some malignancies [1,2]. FAS catalyses fatty acid synthesis from the substrates acetylCoA and malonyl-CoA [3].…”

Section: Introductionmentioning

confidence: 99%

(−)-UB006: A new fatty acid synthase inhibitor and cytotoxic agent without anorexic side effects

Makowski

Mir

Mera

et al. 2017

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

C75 is a synthetic anticancer drug that inhibits fatty acid synthase (FAS) and shows a potent anorexigenic side effect. In order to find new cytotoxic compounds that do not impact food intake, we synthesized a new family of C75 derivatives. The most promising anticancer compound among them was UB006 ((4SR,5SR)-4-(hydroxymethyl)-3-methylene-5-octyldihydrofuran-2(3H)-one). The effects of this compound on cytotoxicity, food intake and body weight were studied in UB006 racemic mixture and in both its enantiomers separately. The results showed that both enantiomers inhibit FAS activity and have potent cytotoxic effects in several tumour cell lines, such as the ovarian cell cancer line OVCAR-3. The (-)-UB006 enantiomer's cytotoxic effect on OVCAR-3 was 40-fold higher than that of racemic C75, and 2-and 38-fold higher than that of the racemic mixture and its opposite enantiomer, respectively. This cytotoxic effect on the OVCAR-3 cell line involves mechanisms that reduce mitochondrial respiratory capacity and ATP production, DDIT4/REDD1 upregulation, mTOR activity inhibition, and caspase-3 activation, resulting in apoptosis.In addition, central and peripheral administration of (+)-UB006 or (-)-UB006 into rats and mice did not affect food intake or body weight. Altogether, our data support the discovery of a new potential anticancer compound (-)-UB006 that has no anorexigenic side effects.

show abstract

Molecular Pathways: Fatty Acid Synthase

Cited by 216 publications

References 43 publications

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

Preclinical Evaluation of Fatty Acid Synthase and EGFR Inhibition in Triple-Negative Breast Cancer

(−)-UB006: A new fatty acid synthase inhibitor and cytotoxic agent without anorexic side effects

Contact Info

Product

Resources

About