Inhibition of endothelial cell proliferation and angiogenesis by orlistat, a fatty acid synthase inhibitor

Browne, Cecille D.; Hindmarsh, Elizabeth J.; Smith, Jeffrey W.

doi:10.1096/fj.05-5404com

Cited by 94 publications

(88 citation statements)

References 28 publications

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“…It was previously reported that orlistat has antiangiogenic properties by inhibiting proliferation and promoting apoptosis in VEGF-A-stimulated human blood vessel endothelial cells (52). Indeed, we very recently demonstrated that orlistat reduces peritumoral angiogenesis in experimental melanomas and that culture medium conditioned by orlistattreated SCC-9 cells has antiangiogenic abilities (53).…”

Section: Discussionmentioning

confidence: 71%

The Fatty Acid Synthase Inhibitor Orlistat Reduces the Growth and Metastasis of Orthotopic Tongue Oral Squamous Cell Carcinomas

Agostini

Almeida

Bastos

et al. 2014

Molecular Cancer Therapeutics

111

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Fatty acid synthase (FASN) is the biosynthetic enzyme responsible for the endogenous synthesis of fatty acids. It is downregulated in most normal cells, except in lipogenic tissues such as liver, lactating breast, fetal lung, and adipose tissue. Conversely, several human cancers, including head and neck squamous cell carcinomas (HNSCC), overexpress FASN, which has been associated with poor prognosis and recently suggested as a metabolic oncoprotein. Orlistat is an irreversible inhibitor of FASN activity with cytotoxic properties on several cancer cell lines that inhibits tumor progression and metastasis in prostate cancer xenografts and experimental melanomas, respectively. To explore whether the inhibition of FASN could impact oral tongue squamous cell carcinoma (OTSCC) metastatic spread, an orthotopic model was developed by the implantation of SCC-9 ZsGreen LN-1 cells into the tongue of BALB/c nude mice. These cells were isolated through in vivo selection, show a more invasive behavior in vitro than the parental cells, and generate orthotopic tumors that spontaneously metastasize to cervical lymph nodes in 10 to 15 days only. SCC-9 ZsGreen LN-1 cells also exhibit enhanced production of MMP-2, ERBB2, and CDH2. The treatment with orlistat reduced proliferation and migration, promoted apoptosis, and stimulated the secretion of VEGFA 165b by SCC-9 ZsGreen LN-1 cells. In vivo, the drug was able to decrease both the volume and proliferation indexes of the tongue orthotopic tumors and, importantly, reduced the number of metastatic cervical lymph nodes by 43%. These results suggest that FASN is a potential molecular target for the chemotherapy of patients with OTSCC. Mol Cancer Ther; 13(3); 585-95. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 71%

The Fatty Acid Synthase Inhibitor Orlistat Reduces the Growth and Metastasis of Orthotopic Tongue Oral Squamous Cell Carcinomas

Agostini

Almeida

Bastos

et al. 2014

Molecular Cancer Therapeutics

111

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“…Chemical and genetic inactivation of FAS disrupts the membrane localization and activity of the oncogene HER2 (c-erbB-2) in breast and ovarian cancer cell lines (32). Treatment of HUVECs with orlistat, a nonspecific FAS inhibitor also used clinically to treat obesity by inhibiting fat digestion, impairs proliferation in part by preventing the cell surface appearance of the VEGF receptor Flk1/VEGFR2/KDR (33). Overexpression of FAS in immortalized prostate cells leads to palmitoylation of Wnt-1, activation of ␤-catenin, and tumor formation in nude mice (34).…”

Section: Discussionmentioning

confidence: 99%

De Novo Lipogenesis Maintains Vascular Homeostasis through Endothelial Nitric-oxide Synthase (eNOS) Palmitoylation*

Wei

Schneider²,

Shenouda

et al. 2011

Journal of Biological Chemistry

116

100

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Endothelial dysfunction leads to lethal vascular complications in diabetes and related metabolic disorders. Here, we demonstrate that de novo lipogenesis, an insulin-dependent process driven by the multifunctional enzyme fatty-acid synthase (FAS), maintains endothelial function by targeting endothelial nitric-oxide synthase (eNOS) to the plasma membrane. In mice with endothelial inactivation of FAS (FASTie mice), eNOS membrane content and activity were decreased. eNOS and FAS were physically associated; eNOS palmitoylation was decreased in FAS-deficient cells, and incorporation of labeled carbon into eNOS-associated palmitate was FAS-dependent. FASTie mice manifested a proinflammatory state reflected as increases in vascular permeability, endothelial inflammatory markers, leukocyte migration, and susceptibility to LPS-induced death that was reversed with an NO donor. FAS-deficient endothelial cells showed deficient migratory capacity, and angiogenesis was decreased in FASTie mice subjected to hindlimb ischemia. Insulin induced FAS in endothelial cells freshly isolated from humans, and eNOS palmitoylation was decreased in mice with insulin-deficient or insulin-resistant diabetes. Thus, disrupting eNOS bioavailability through impaired lipogenesis identifies a novel mechanism coordinating nutritional status and tissue repair that may contribute to diabetic vascular disease.Damage to blood vessels is inextricably linked with diabetes. Microvascular disease causes visual loss, renal failure, and neuropathy, and macrovascular disease (atherosclerotic coronary disease, stroke, and peripheral arterial disease) causes premature death. Macro-and microvascular complications characterize both type 1 (insulin-deficient) and type 2 (insulin-resistant with hyperinsulinemia) diabetes. Hyperglycemia is a biomarker of blood vessel disease (1), and glucose lowering delays microvascular complications (2, 3), but this therapy does not prevent progression of established microvascular (4) or macrovascular disease (5, 6). In addition to improving glycemia, optimal approaches to complications may require manipulating processes that are mostly obscure.One such process is endothelial lipid metabolism. The endothelium controls tissue access from the circulation and regulates vascular functions, including inflammation and angiogenesis. Endothelial dysfunction, largely due to defects in eNOS, 3 is characteristic of diabetes and probably promotes vascular disease (7,8). Circulating fatty acids interfere with eNOS and increase inflammation (9, 10), and insulin resistance appears to have similar effects by increasing fatty acid oxidation (11), but little is known about how fuels are partitioned inside endothelial cells. A critical pathway for fuel flow is de novo lipogenesis, the generation of fatty acids from simple sugars, which requires FAS (12, 13). One might predict that de novo lipogenesis would be irrelevant to endothelial cells, which are continually bathed in fatty acids, the product of the FAS reaction.Here, we report that endothelial...

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“…It has been suggested that inhibition of FASN may prevent or inhibit metastasis in colorectal cancer (41) and the FASN inhibitor orlistat was shown to decrease angiogenesis and metastases in experimental models (42,43). We tested the ability of C75 to inhibit migration of prostate cancer cells.…”

Section: Figmentioning

confidence: 99%

Inhibition of Fatty Acid Synthase Sensitizes Prostate Cancer Cells to Radiotherapy

et al. 2015

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Inhibition of endothelial cell proliferation and angiogenesis by orlistat, a fatty acid synthase inhibitor

Cited by 94 publications

References 28 publications

The Fatty Acid Synthase Inhibitor Orlistat Reduces the Growth and Metastasis of Orthotopic Tongue Oral Squamous Cell Carcinomas

The Fatty Acid Synthase Inhibitor Orlistat Reduces the Growth and Metastasis of Orthotopic Tongue Oral Squamous Cell Carcinomas

De Novo Lipogenesis Maintains Vascular Homeostasis through Endothelial Nitric-oxide Synthase (eNOS) Palmitoylation*

Inhibition of Fatty Acid Synthase Sensitizes Prostate Cancer Cells to Radiotherapy

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