ArticleMolecular imaging and biology2013
Metabolic shifts induced by fatty acid synthase inhibitor orlistat in non-small cell lung carcinoma cells provide novel pharmacodynamic biomarkers for positron emission tomography and magnetic resonance spectroscopy.
Article in Molecular imaging and biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 37 citations in OpenAlex.
- Targeting obesity, metabolic syndrome, and prostate cancer: GLP-1 agonists as emerging therapeutic agents.Discover oncology · 2025Review
- The role of altered fatty acid in pathological scars and their dermal fibroblasts.Chinese journal of traumatology = Zhonghua chuang shang za zhi · 2022Article
- Fatty Acid Synthase: An Emerging Target in Cancer.Molecules (Basel, Switzerland) · 2020Review
- High-Throughput Screening of Lipidomic Adaptations in Cultured Cells.Biomolecules · 2019Article
- Article
- Discovering Targets of Non-enzymatic Acylation by Thioester Reactivity Profiling.Cell chemical biology · 2017Article
- Metabolic Imaging to Assess Treatment Response to Cytotoxic and Cytostatic Agents.Frontiers in oncology · 2016Review
- Dysregulated metabolism contributes to oncogenesis.Seminars in cancer biology · 2015Review
- Fatty acid synthase overexpression: target for therapy and reversal of chemoresistance in ovarian cancer.Journal of translational medicine · 2015Article
- Altered gene products involved in the malignant reprogramming of cancer stem/progenitor cells and multitargeted therapies.Molecular aspects of medicine · 2014Review
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4 authors at 1 institution in 1 country.
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Abstract
purposeAbnormal fatty acid (FA) synthesis is one of the common features of cancer. Fatty acid synthase (FASN), a multifunctional enzyme playing a key role in biosynthesis of FA, is up-regulated in prostate, breast, and lung carcinomas. Orlistat is a FDA-approved anti-obesity drug that inhibits the thioesterase domain of FASN, interferes with cellular FA synthesis, can arrest tumor cell proliferation, and induces tumor cell apoptosis. The current study was aimed to investigate the metabolic changes associated with FASN inhibition by orlistat and to understand the molecular mechanisms behind the observed metabolic changes in non-small cell lung carcinoma (NSCLC) cell lines. PROCEDURES: Changes in metabolite pools in four NSCLC cell lines (H441, H1975, H3255, and PC14) with different mutational profiles were studied using NMR spectroscopy before and after in vitro incubation with sub-toxic concentration of orlistat and [1-(13)C]D-glucose or [1,2-(13)C2]choline. In vitro radiotracer accumulation assays in cells were performed with [(3)H]acetate, [(14)C]fluoroacetate, and 2-deoxy-2-[(18)F]fluoro-D-glucose. In parallel, microarray profiling of genes involved in the regulation of carbohydrate and lipid metabolism was performed.
resultsIn orlistat-treated NSCLC cells, FASN inhibition results in characteristic changes in intermediary metabolites (FAs, choline, phospholipids, and TCA cycle metabolites) as observed by magnetic resonance spectroscopy. Further, FASN inhibition by orlistat induces multiple adaptive changes in FA synthetic pathway and associated metabolic pathways, including induction of ketone metabolism and glutaminolysis, as well as the up-regulation of 5' adenosine monophosphate-activated protein kinase.
conclusionsThese observed changes in metabolic pools in orlistat-treated cells demonstrate the critical role of fatty acid de novo synthesis and metabolism for cellular energy production, especially in tumor cells with low glycolytic activity, which goes beyond the widely accepted concept that FA synthesis is important for cell membrane biosynthesis in rapidly proliferating tumor cells.
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