Inhibition of de novo Palmitate Synthesis by Fatty Acid Synthase Induces Apoptosis in Tumor Cells by Remodeling Cell Membranes, Inhibiting Signaling Pathways, and Reprogramming Gene Expression.
Inhibition of de novo Palmitate Synthesis by Fatty Acid Synthase Induces Apoptosis in Tumor Cells by Remodeling Cell Membranes, Inhibiting Signaling Pathways, and Reprogramming Gene Expression.
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DOI：
10.1016/j.ebiom.2015.06.020
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发表时间：
2015-08
期刊：
影响因子：
11.1
通讯作者：
Heuer TS
中科院分区：
文献类型：
--
作者：
Ventura R;Mordec K;Waszczuk J;Wang Z;Lai J;Fridlib M;Buckley D;Kemble G;Heuer TS
通过脂肪酸合酶（FATCH）抑制来抑制棕榈酸酯的从头合成提供了一种未经证实的癌症治疗方法，其具有很强的生物学原理。在许多肿瘤类型中，FXR表达随着肿瘤进展而增加，并与化疗耐药性、肿瘤转移和患者存活率降低相关。TVB-3166是一种口服的、可逆的、强效的、选择性的FXR抑制剂，可诱导细胞凋亡，在富脂条件下抑制非锚定依赖性细胞生长，并抑制体内异种移植肿瘤生长。在20-200 nM TVB-3166之间观察到剂量依赖性效应，这与生物化学法和细胞棕榈酸合成试验中的IC 50一致。机制研究表明，FXR抑制破坏脂筏结构，抑制生物学途径如脂质生物合成、PI 3 K-AKT-mTOR和β-连环蛋白信号转导，并抑制致癌效应物如c-Myc的表达;这些效应是肿瘤细胞特异性的。我们的研究结果表明，在生物多样性的临床前肿瘤模型中，Festival抑制具有抗肿瘤活性，并提供了机制和药理学证据，表明Festival抑制提供了一种有前途的治疗策略，用于治疗各种癌症，包括表达突变型K-Ras，ErbB 2，c-Met和PTEN的癌症。报告的发现为正在进行的研究提供了信息，以将作用机制与定义的肿瘤类型联系起来，并推进支持开发Festival抑制剂作为癌症治疗药物的生物标志物的发现。脂肪酸合成酶（Fatty acid synthase，FATS-R）是肿瘤细胞生物学中的重要酶，FATS-R的过度表达与患者预后的降低和对多种癌症治疗的耐药性有关。我们的数据表明，TVB-3166的选择性和有效的FcB抑制导致肿瘤细胞的选择性死亡，对正常细胞没有显著影响，并在耐受良好的剂量下抑制体内异种移植肿瘤生长。鉴定了用于选择对Festival抑制高度敏感的肿瘤的候选生物标志物。这些临床前数据提供了机制和药理学证据，表明Festival抑制为治疗各种癌症提供了有希望的治疗策略。TVB-3166是一种口服、可逆、强效和选择性的FRENSION抑制剂。TVB-3166对FcB的抑制诱导肿瘤细胞而非正常细胞的凋亡。TVB-3166抑制体内异种移植肿瘤生长。鉴定用于选择对Festival抑制敏感的肿瘤的候选生物标志物。
Inhibition of de novo palmitate synthesis via fatty acid synthase (FASN) inhibition provides an unproven approach to cancer therapy with a strong biological rationale. FASN expression increases with tumor progression and associates with chemoresistance, tumor metastasis, and diminished patient survival in numerous tumor types. TVB-3166, an orally-available, reversible, potent, and selective FASN inhibitor induces apoptosis, inhibits anchorage-independent cell growth under lipid-rich conditions, and inhibits in-vivo xenograft tumor growth. Dose-dependent effects are observed between 20–200 nM TVB-3166, which agrees with the IC50 in biochemical FASN and cellular palmitate synthesis assays. Mechanistic studies show that FASN inhibition disrupts lipid raft architecture, inhibits biological pathways such as lipid biosynthesis, PI3K–AKT–mTOR and β-catenin signal transduction, and inhibits expression of oncogenic effectors such as c-Myc; effects that are tumor-cell specific. Our results demonstrate that FASN inhibition has anti-tumor activities in biologically diverse preclinical tumor models and provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers, including those expressing mutant K-Ras, ErbB2, c-Met, and PTEN. The reported findings inform ongoing studies to link mechanisms of action with defined tumor types and advance the discovery of biomarkers supporting development of FASN inhibitors as cancer therapeutics. Fatty acid synthase (FASN) is a vital enzyme in tumor cell biology; the over-expression of FASN is associated with diminished patient prognosis and resistance to many cancer therapies. Our data demonstrate that selective and potent FASN inhibition with TVB-3166 leads to selective death of tumor cells, without significant effect on normal cells, and inhibits in vivo xenograft tumor growth at well-tolerated doses. Candidate biomarkers for selecting tumors highly sensitive to FASN inhibition are identified. These preclinical data provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers. TVB-3166 is an orally available, reversible, potent, and selective FASN inhibitor. TVB-3166 inhibition of FASN induces apoptosis in tumor cells but not normal cells. TVB-3166 inhibits in vivo xenograft tumor growth. Candidate biomarkers to select tumors sensitive to FASN inhibition are identified.