脂肪酸合酶与PTEN/PI3K/AKT信号通路

脂肪酸从头合成的增加是肿瘤脂代谢改变的一个重要方面,脂肪酸合酶(FASN)是脂肪酸从头合成的关键酶,该酶在众多类型肿瘤中均有异常的高表达,但其原因尚不是十分清楚。PTEN/PI3K/AKT信号通路是研究较多的信号通路之一,我们对其有较多认识。本文通过综述PTEN/PI3K/AKT信号通路与脂肪酸合酶的调节关系,为探究肿瘤脂代谢的机制以及寻找抗癌药物提供线索。     

下调脂肪酸合成酶表达对膀胱癌UMUC3细胞增殖、迁移及侵袭能力的影响*

目的: 研究脂肪酸合成酶(FASN)表达对膀胱癌UMUC3细胞增殖、迁移、侵袭的影响,探讨其内在可能机制。方法:免疫组化法检测30例膀胱癌和15例正常膀胱组织FASN蛋白的表达;用脂质体2000分别转染FASN siRNA和无义siRNA至UMUC3细胞,筛选、鉴定siFASN和siControl稳定的细胞,siFASN组细胞设为实验组,siControl组设为对照组;采用蛋白印迹法(Western blot)和实时荧光定量PCR(RT-PCR)法分别检测siFASN组和siControl组细胞FASN蛋白及mRNA的表达,MTT法检测siFASN组和siControl组细胞增殖情况,划痕试验、Transwell试验分别检测siFASN组和siControl组细胞迁移、侵袭能力。结果:FASN蛋白在膀胱癌组织中过表达,且与病理分期、分级密切相关(P＜0.05)。与siControl组相比,siFASN组细胞FASN mRNA及蛋白表达下调(P＜0.05),细胞增殖活力明显下降(P＜0.05),迁移能力明显下降(P＜0.05),穿膜细胞数量明显减少(P＜0.05)。结论:FASN过表达在膀胱癌发生、发展中发挥重要作用,下调FASN表达能抑制膀胱癌细胞的增殖、迁移、侵袭能力,抑制FASN表达有望成为一种新的膀胱癌治疗方法。     

脂肪酸去饱和途径在肿瘤发生发展中的作用

肿瘤的发生发展与肿瘤代谢异常密切相关。近几年,脂肪酸代谢在肿瘤代谢研究中越来越受到关注,脂肪酸的合成代谢在肿瘤细胞的生长、转移和化疗效果提升中发挥关键性的作用。脂肪酸除了作为细胞膜基质结构成分外,还是重要的二级信使,同时可以作为机体能量的来源。不饱和脂肪酸由饱和脂肪酸通过去饱和途径作用转化而来。由硬脂酰辅酶A去饱和酶(SCD)所催化的单不饱和脂肪酸是生物体细胞膜必需的组分之一。肿瘤细胞脂肪酸代谢中的去饱和途径由于新的替代方式的出现近年来备受关注,即由脂肪酸去饱和酶2 (FADS2)介导生成sapienate的去饱和途径。该文综述归纳总结了脂肪酸去饱和途径中关键酶(SCD和FADS2)及甾醇调节元件结合蛋白1 (SREBP1)在肿瘤的发生发展中的作用及最新研究,旨在对基于肿瘤脂肪酸代谢的治疗及调控靶点进行进一步的挖掘和探索。     

脂肪酸转运蛋白家族(FATPs)的研究进展

长链脂肪酸在哺乳动物体内具有广泛的生理功能,特别是在生物膜的形成和动态特性维持中发挥着不可或缺的作用,同时,作为能量产生的重要原料,长链脂肪酸在保持心脏和骨骼肌正常功能方面也具有极其重要的作用.脂肪酸转运蛋白家族(fatty acid transport proteins,FATPs)是一组膜蛋白,在心脏、肝脏、肌肉和小肠等脂肪酸代谢活跃的组织器官中均有表达.已有研究表明,FATPs在长链脂肪酸的摄取和代谢调节中发挥着重要作用,现对FATPs的组织分布、结构特点、功能、作用机制及其与人类疾病的关系等方面进行综述.     

脂肪酸从头合成代谢及其抑制剂在肿瘤中的研究进展

代谢重编程是肿瘤的重要特征之一。肿瘤细胞常会发生过度增殖、局部侵袭、转移、复发和耐药等。这些过程均需要大量的脂肪酸,用于合成肿瘤细胞所必需的生物膜和信号分子等。因此,研究脂肪酸从头合成代谢在肿瘤细胞发生发展过程中所发挥的重要作用有助于深入理解肿瘤的发病机制,为肿瘤的诊断和治疗提供新的思路。本文将对脂肪酸合成代谢在肿瘤中的研究进展进行论述,并关注脂肪酸合成相关代谢酶抑制剂的研究现状,旨在为肿瘤的治疗提供更多的线索。     

山羊SREBP-1基因的超表达对脂肪酸代谢相关基因表达的影响

本研究旨在通过构建西农萨能羊固醇调节元件结合蛋白-1(SREBP-1)基因的重组腺病毒超表达载体,获得有感染性的病毒颗粒,并检测该基因过表达后对乳腺上皮细胞中脂肪酸代谢相关基因的影响,为进一步研究该基因在脂肪酸代谢及泌乳调控中的功能奠定基础。根据GenBank中收录的西农萨能羊SREBP-1基因的序列设计引物,PCR扩增后进行测序。将测序正确的目的基因连接到穿梭载体pAdTrack-CMV后并进行线性化,转化含有腺病毒骨架载体pAdEasy-1的大肠杆菌Escherichia coli BJ5183感受态细胞中进行同源重组,将重组成功的质粒进行PacⅠ酶线性化,转染HEK 293细胞进行重组腺病毒的包装、扩繁及滴度测定。病毒液感染原代乳腺上皮细胞,实时荧光定量检测SREBP-1超表达效果及对脂肪酸代谢相关基因的影响。结果表明:重组腺病毒质粒构建成功,腺病毒滴度为109U/mL。病毒液感染乳腺上皮细胞48 h后,SREBP-1基因表达量上升大约15倍,72 h后,表达量上调了30倍;对脂肪酸代谢相关基因的影响在72 h较为明显,其中,脂肪酸合酶(FASN)及酰基辅酶A羧化酶(ACC)均显著上调了大约两倍,过氧化物酶体增殖物激活受体(PPARγ)上调了大约1.5倍,肝素X受体(LXRα)及甘油三酯水解酶(ATGL)表达量升高了1.2倍;其中硬脂酰辅酶A去饱和酶(SCD)表达水平无明显变化。表明在西农萨能羊乳腺上皮细胞中,SREBP-1能够促进脂肪酸合成相关基因的表达,对山羊乳腺脂肪酸代谢具有调控作用。     

脂肪酸结合蛋白的研究

脂肪酸结合蛋白是一族多源性的小分子胞内蛋白质、广泛存在于哺乳动物体内的多种细胞,它在长链脂肪酸的转运,低谢调节中扮演着一个重要角色。脂肪酸结合蛋白的异常还可能与心肌肥大,心肌缺血,冠心病,急性和慢性酒精中毒,糖尿病以及癌症等有关。     

Adipophilin在不同组织和器官中的功能

Adipophilin（ADFP）是一种脂滴周围主要的相关蛋白,它大量分布在脂质蓄积正常或不正常的细胞中,是脂质蓄积的一个特异性标记物。它在脂肪细胞分化早期就有很高的表达,但当脂肪细胞成熟后,它的表达就明显减少。ADFP在很多组织器官中都发挥重要作用,它不仅参与脂肪细胞的脂质代谢、脂滴的形成及肝内三酰甘油（TO）的合成与代谢,还能促进巨噬细胞、平滑肌细胞的泡沫化,长链脂肪酸的摄取,乳汁的分泌等。ADFP的表达异常与动脉粥样硬化、胰岛素抵抗和肿瘤等病理过程密切相关。     

FBXO39基因对肿瘤细胞代谢分子的影响

FBXO39是F-box蛋白家族中的一员,研究表明该蛋白是一个新的候选肿瘤-睾丸抗原,可能与人类肿瘤的发生密切相关。为了探讨FBXO39基因的生物学功能,实验中首先检测了FBXO39在不同肿瘤细胞系中的表达水平,并通过分子克隆技术构建了FBXO39的真核表达载体,进而利用高通量的PCR array代谢组学分析方法在低表达FBXO39的MCF7细胞中筛选受FBXO39调节的代谢相关基因,最后采用定量PC R实验在低表达FBXO39的Ntera2细胞中验证筛选出来的代谢基因。结果显示,在MCF7和Ntera2肿瘤细胞中,6个代谢基因(ALDH9A1、MCT1、DLAT、HMGCS、FASN、GLUL)的表达受FBXO39的正向调控,表明FBXO39可能通过上调这些基因的表达参与肿瘤细胞的代谢过程。     

肝型脂肪酸结合蛋白研究进展

肝型脂肪酸结合蛋白(liver-type fatty acid binding protein,L-FABP,FABPI)是脂肪酸结合蛋白家族的成员之一,主要在肝脏、小肠、肾脏及胰腺等组织细胞中有表达.研究发现,L-FABP与脂肪酸的摄取、转运、代谢调节有关.近年研究表明,肝型脂肪酸结合蛋白(L-FABP)与肿瘤、肾脏疾病、脂肪肝、肥胖、糖尿病等多种疾病的发生发展密切相关.本文就肝型脂肪酸结合蛋白的分子结构、功能以及与疾病的关系作一综述.     

Role of fatty acid synthase in gemcitabine and radiation resistance of pancreatic cancers

Human fatty acid synthase (FASN) is a homo-dimeric protein with multi-enzymatic activity responsible for the synthesis of palmitate. FASN expression has been found to be up-regulated in multiple types of human cancers and its expression correlates with poor prognosis possibly by causing treatment resistance. In this study, we tested if FASN expression is up-regulated in human pancreatic cancers and if its higher expression level in pancreatic cancers causes intrinsic resistance to gemcitabine and radiation. We found that FASN expression is significantly up-regulated in human pancreatic cancer tissues without any correlation to age, sex, race, and tumor stage. Knocking down or over-expressing FASN significantly down- or up-regulate resistance of pancreatic cancer cell lines to both gemcitabine and radiation treatments. These findings imply that the elevated FASN expression in pancreatic cancers may contribute to unsuccessful treatments of pancreatic cancers by causing intrinsic resistance to both chemotherapy and radiation therapy.     

Fatty acid synthase causes drug resistance by inhibiting TNF-α and ceramide production

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.     

Reduced expression of FASN through SREBP‐1 down‐regulation is responsible for hypoxic cell death in HepG2 cells

Cells under hypoxic stress either activate an adaptive response or undergo cell death. Although some mechanisms have been reported, the exact mechanism behind hypoxic cell death remains unclear. Recently, increased expression of fatty acid synthase (FASN) has been observed in various human cancers. In highly proliferating cells, tumor‐associated FASN is considered necessary for both membrane lipids production and post‐translational protein modification, but the exact mechanisms are not fully understood. Further, FASN overexpression is associated with aggressive and malignant cancer diseases and FASN inhibition induces apoptosis in cancer cells. For this reason, FASN is emerging as a key target for the potential diagnosis and treatment of various cancers. Here, we observed decreased FASN expression under hypoxic cell death conditions in HepG2 cells. Thus, we examined the effect of decreased FASN expression on hypoxia‐induced cell death in HepG2 cells and also investigated the mechanism responsible for reduction of FASN expression under hypoxic cell death conditions. As a result, reduction of FASN expression resulted in hypoxic cell death via malonyl‐CoA accumulation. In addition, SREBP‐1 restored FASN reduction and hypoxia‐induced apoptosis. Taken together, we suggest that hypoxic cell death is promoted by the reduced expression of FASN through SREBP‐1 down‐regulation. J. Cell. Biochem. 113: 3730–3739, 2012. © 2012 Wiley Periodicals, Inc.     

Fatty acid synthase expression and esophageal cancer

Fatty acid synthase (FASN) overexpression has also been associated with a variety of human malignancies including tumor progression, aggressiveness, and metastasis. To investigate the role of FASN expression in esophageal cancer, we evaluated 60 cases of squamous cell carcinoma, 20 cases of adenocarcinoma, and 10 cases of normal esophageal tissues. We found that FASN was detected in 95?% human squamous cell carcinoma, and in 90?% human adenocarcinoma samples. However, all cases of normal esophageal epithelium did not express the protein of FASN. Further, to investigate the role of FASN in tumorigenesis and development, we analyze the growth and migration by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation and wound healing assay. We found that inhibition of FASN expression in TE13 cells by RNAi suppressed the growth of cells. Decreased FASN expression mitigated the migration of TE13 cells. These studies demonstrated the functional importance of FASN in esophageal tumorigenesis, and suggested that inhibiting FASN might be applied to treat esophageal cancer.     

The Selective Target of Capsaicin on FASN Expression and De Novo Fatty Acid Synthesis Mediated through ROS Generation Triggers Apoptosis in HepG2 Cells

The inhibition of the mammalian de novo synthesis of long-chain saturated fatty acids (LCFAs) by blocking the fatty acid synthase (FASN) enzyme activity in tumor cells that overexpress FASN can promote apoptosis, without apparent cytotoxic to non-tumor cells. The present study aimed to focus on the potent inhibitory effect of capsaicin on the fatty acid synthesis pathway inducing apoptosis of capsaicin in HepG2 cells. The use of capsaicin as a source for a new FASN inhibitor will provide new insight into its possible application as a selective anti-cancer therapy. The present findings showed that capsaicin promoted apoptosis as well as cell cycle arrest in the G0/G1 phase. The onset of apoptosis was correlated with a dissipation of mitochondrial membrane potential (ΔΨm). Apoptotic induction by capsaicin was mediated by inhibition of FASN protein expression which was accompanied by decreasing its activity on the de novo fatty acid synthesis. The expression of FASN was higher in HepG2 cells than in normal hepatocytes that were resistant to undergoing apoptosis following capsaicin administration. Moreover, the inhibitory effect of capsaicin on FASN expression and activity was found to be mediated by an increase of intracellular reactive oxygen species (ROS) generation. Treatment of HepG2 cells with capsaicin failed to alter ACC and ACLY protein expression, suggesting ACC and ACLY might not be the specific targets of capsaicin to induce apoptosis. An accumulation of malonyl-CoA level following FASN inhibition represented a major cause of mitochondrial-dependent apoptotic induction instead of deprivation of fatty acid per se. Here, we also obtained similar results with C75 that exhibited apoptosis induction by reducing the levels of fatty acid without any change in the abundance of FASN expression along with increasing ROS production. Collectively, our results provide novel evidence that capsaicin exhibits a potent anti-cancer property by targeting FASN protein in HepG2 cells.     

Dietary soy protein inhibits DNA damage and cell survival of colon epithelial cells through attenuated expression of fatty acid synthase

Dietary intake of soy protein decreases tumor incidence in rat models of chemically induced colon cancer. We hypothesized that decreased expression of fatty acid synthase (FASN) underlies, in part, the tumor-preventive effects of soy protein, since FASN overexpression characterizes early tumorigenesis. Here, we show that colonic FASN levels are reduced with dietary intake of soy protein isolate (SPI), compared with a control casein diet, in male Sprague-Dawley rats administered the colon carcinogen azoxymethane. SPI consumption resulted in decreased serum insulin levels and decreased azoxymethane-induced tumor suppressor p53 phosphorylation in colon crypt epithelium. To evaluate potential links between insulin and FASN leading to DNA damage, C2(BBe)1 colon epithelial cells, treated with insulin and/or the carcinogen N-nitroso-N-methylurea (NMU), were evaluated for DNA damage and apoptosis after transfection with control or FASN small interfering RNAs (siRNAs). While the numbers of DNA apurinic/apyrimidinic sites (biomarker of DNA damage) induced by NMU were unaffected by transfection of FASN siRNA, insulin induction of these sites was decreased with FASN knockdown. By contrast, NMU-induced apoptosis of C2(BBe)1, as well as intestinal epithelial cell (IEC)-6, was enhanced by transfected FASN siRNA. Increased FASN expression in IEC-6 cells by addition of liver X receptor agonist T0901317 did not affect apurinic/apyrimidinic site number, but enhanced cell killing by cerulenin, a FASN inhibitor. Moreover, insulin rescued NMU-treated cells from apoptosis in an FASN-dependent manner. Results suggest that dietary SPI, by decreasing circulating insulin levels and colon FASN expression, attenuates insulin-induced DNA damage and FASN-mediated anti-apoptosis during carcinogenesis, resulting in an overall reduced tumorigenic state.     

Inhibition of Fatty Acid Synthase Decreases Expression of Stemness Markers in Glioma Stem Cells

Cellular metabolic changes, especially to lipid metabolism, have recently been recognized as a hallmark of various cancer cells. However, little is known about the significance of cellular lipid metabolism in the regulation of biological activity of glioma stem cells (GSCs). In this study, we examined the expression and role of fatty acid synthase (FASN), a key lipogenic enzyme, in GSCs. In the de novo lipid synthesis assay, GSCs exhibited higher lipogenesis than differentiated non-GSCs. Western blot and immunocytochemical analyses revealed that FASN is strongly expressed in multiple lines of patient-derived GSCs (G144 and Y10), but its expression was markedly reduced upon differentiation. When GSCs were treated with 20 μM cerulenin, a pharmacological inhibitor of FASN, their proliferation and migration were significantly suppressed and de novo lipogenesis decreased. Furthermore, following cerulenin treatment, expression of the GSC markers nestin, Sox2 and fatty acid binding protein (FABP7), markers of GCSs, decreased while that of glial fibrillary acidic protein (GFAP) expression increased. Taken together, our results indicate that FASN plays a pivotal role in the maintenance of GSC stemness, and FASN-mediated de novo lipid biosynthesis is closely associated with tumor growth and invasion in glioblastoma.     

Fatty Acid Synthase Mediates the Epithelial-Mesenchymal Transition of Breast Cancer Cells

This study aimed to investigate the role of fatty acid synthase (FASN) in the epithelial-mesenchymal transition (EMT) of breast cancer cells. MCF-7 cells and MCF-7 cells overexpressing mitogen-activated protein kinase 5 (MCF-7-MEK5) were used in this study. MCF-7-MEK5 cells showed stable EMT characterized by increased vimentin and decreased E-cadherin expression. An In vivo animal model was established using the orthotopic injection of MCF-7 or MCF-7-MEK5 cells. Real-time quantitative PCR and western blotting were used to detect the expression levels of FASN and its downstream proteins liver fatty acid-binding protein (L-FABP) and VEGF/VEGFR-2 in both in vitro and in vivo models (nude mouse tumor tissues). In MCF-7-MEK5 cells, significantly increased expression of FASN was associated with increased levels of L-FABP and VEGF/VEGFR-2. Cerulenin inhibited MCF-7-MEK5 cell migration and EMT, and reduced FASN expression and down-stream proteins L-FABP, VEGF, and VEGFR-2. MCF-7-MEK5 cells showed higher sensitivity to Cerulenin than MCF-7 cells. Immunofluorescence revealed an increase of co-localization of FASN with VEGF on the cell membrane and with L-FABP within MCF-7-MEK5 cells. Immunohistochemistry further showed that increased percentage of FASN-positive cells in the tumor tissue was associated with increased percentages of L-FABP- and VEGF-positive cells and the Cerulenin treatment could reverse the effect. Altogether, our results suggest that FASN is essential to EMT possibly through regulating L-FABP, VEGF and VEGFR-2. This study provides a theoretical basis and potential strategy for effective suppression of malignant cells with EMT.     

Caveolin-1 interacts with a lipid raft-associated population of fatty acid synthase

Fatty Acid Synthase (FASN), a cytoplasmic biosynthetic enzyme, is the major source of long-chain fatty acids, particularly palmitate. Caveolin-1 (Cav-1) is a palmitoylated lipid raft protein that plays a key role in signal transduction and cholesterol transport. Both proteins have been implicated in prostate cancer (PCa) progression, and Cav-1 regulates FASN expression in a mouse model of aggressive PCa. We demonstrate that FASN and Cav-1 are coordinately up-regulated in human prostate tumors in a hormone-insensitive manner. Levels of FASN and Cav-1 protein expression discriminated between localized and metastatic cancers, and the two proteins exhibited analogous subcellular locations in a tumor subset. Endogenous FASN and Cav-1 were reciprocally co-immunoprecipitated from human and murine PCa cells, indicating that FASN forms a complex with Cav-1. FASN, a cytoplasmic enzyme, was induced to associate transiently with lipid raft membranes following alterations in signal transduction within the Src, Akt and EGFR pathways, suggesting that co-localization of FASN and Cav-1 is dependent on activation of upstream signaling mediators. A Cav-1 palmitoylation mutant, Cav-1C133/143/156S, that prevents phosphorylation by Src, did not interact with FASN. When overexpressed in Cav-1-negative PCa cells, Cav-1C133/143/156S caused a reduction of both Src and Akt levels, as well as of their active, phosphorylated forms, in comparison with wild type Cav-1. These findings suggest that FASN and Cav-1 physically and functionally interact in PCa cells. They also imply that palmitoylation within this complex is involved in tumor growth and survival.