Fatty acid synthase inhibitor orlistat induces apoptosis in T cell lymphoma: Role of cell survival regulatory molecules
Fatty acid synthase inhibitor orlistat induces apoptosis in T cell lymphoma: Role of cell survival regulatory molecules
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DOI：
10.1016/j.bbagen.2012.07.010
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发表时间：
2012-11-01
影响因子：
3
通讯作者：
Singh, Sukh Mahendra
中科院分区：
文献类型：
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作者：
Kant, Shiva;Kumar, Ajay;Singh, Sukh Mahendra
背景：脂肪酸合成酶（FATCH）催化的脂肪酸从头合成对肿瘤细胞的存活至关重要。因此，治疗性靶向FXR被认为是一种新的治疗策略。然而，在这方面的了解很少关于血液来源的恶性肿瘤。因此，目前的调查，进行研究的分子机制的FRESINS抑制剂奥利司他（tetrahydrolipstatin）的抗肿瘤作用，使用小鼠模型的T细胞lymphoma.Methods：奥利司他的抗肿瘤疗效进行了研究，在体外通过估计细胞存活的MIT法和凋亡的瑞吉姆萨，TUNEL，Annexin-V/PI染色和% DNA片段。用荧光显微镜观察肿瘤细胞内活性氧（ROS）的产生。通过RT-PCR和Western blot分析基因和蛋白的表达。用分光光度计测定酶活和CPT-1活性。细胞因子的表达进行了分析，通过ELISA.Results：我们报告，抑制FRENTA与其特异性抑制剂奥利司他表现出肿瘤特异性抑制细胞存活，伴随着诱导细胞凋亡。奥利司他处理的肿瘤细胞显示出改变的ROS生成，细胞因子平衡的转变和细胞存活调节分子如HSP 70、Bcl 2、p53、Caspase-3和CAD的调节表达。据观察，IFN-γ介导的奥利司他依赖的调制的Festivalexpression.Conclusion和一般意义：在这项研究中，我们报告了一些迄今未探索的新的方面与奥利司他依赖的调制肿瘤细胞生存的分子机制。这些观察结果将有助于设计使用奥利司他治疗血液系统恶性肿瘤的临床治疗方案。(C)2012爱思唯尔有限公司版权所有。
Background: De novo fatty acid synthesis catalyzed by fatty acid synthase (FASN) is crucial for tumor cell survival. Thus therapeutic targeting of FASN is considered as a novel antineoplastic strategy. However, little is understood in this respect regarding malignancies of hematological origin. The present investigation was therefore, undertaken to study the molecular mechanisms of the antitumor action of FASN inhibitor orlistat (tetrahydrolipstatin) using a murine model of a T cell lymphoma.Methods: The antitumor efficacy of orlistat was investigated in vitro by estimating cell survival by MIT assay and apoptosis by Wright Giemsa, TUNEL, Annexin-V/PI staining and % DNA fragmentation. Generation of reactive oxygen species (ROS) in tumor cells was studied using fluorescence microscopy. Expression of genes and proteins was carried out by RT-PCR and western blot analyses respectively. FASN and CPT-1 activity was estimated by spectrophotometer. Cytokines expression was analyzed by ELISA.Results: We report that inhibition of FASN with its specific inhibitor orlistat manifests tumor-specific inhibition of cell survival, accompanied by induction of apoptosis. Orlistat-treated tumor cells showed an altered ROS generation, shift in cytokine balance and modulated expression of cell survival regulatory molecules like HSP70, Bcl2, p53, PUMA, Caspase-3 and CAD. It was observed that IFN-gamma mediates orlistat-dependent modulation of FASN expression.Conclusion and general significance: In this study, we report some of the so far unexplored novel aspects underlying the molecular mechanisms associated with orlistat-dependent modulation of tumor cell survival. These observations will help in designing antineoplastic therapeutic protocols using orlistat against malignancies of hematological origin. (C) 2012 Elsevier B.V. All rights reserved.