title: Fatty acid synthase causes drug resistance by inhibiting TNF-α and ceramide production.
abstract: Fatty acid synthase (FASN) is a key enzyme in the synthesis of palmitate, the precursor of major nutritional, energetic, and signaling lipids. FASN expression is upregulated in many human cancers and appears to be important for cancer cell survival. Overexpression of FASN has also been found to associate with poor prognosis and higher risk of recurrence of human cancers. Indeed, elevated FASN expression has been shown to contribute to drug resistance. However, the mechanism of FASN-mediated drug resistance is currently unknown. In this study, we show that FASN overexpression causes resistance to multiple anticancer drugs via inhibiting drug-induced ceramide production, caspase 8 activation, and apoptosis. We also show that FASN overexpression suppresses tumor necrosis factor-α production and nuclear factor-κB activation as well as drug-induced activation of neutral sphingomyelinase. Thus, TNF-α may play an important role in mediating FASN function in drug resistance.
authors: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN.
authors: Hailan
authors: H
authors: Liu
authors: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN.
authors: Xi
authors: X
authors: Wu
authors: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN.
authors: Zizheng
authors: Z
authors: Dong
authors: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN.
authors: Zhiyong
authors: Z
authors: Luo
authors: Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN.
authors: Zhenwen
authors: Z
authors: Zhao
authors: Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN; IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN.
authors: Yan
authors: Y
authors: Xu
authors: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN; IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN.
authors: Jian-Ting
authors: JT
authors: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002518:Ceramides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D064429:Fatty Acid Synthases