Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model
Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model
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DOI：
10.1002/ijc.23835
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发表时间：
2008-12-01
影响因子：
6.4
通讯作者：
Graner, Edgard
中科院分区：
文献类型：
--
作者：
Carvalho, Marco A.;Zecchin, Karina G.;Graner, Edgard
脂肪酸合成酶（FASN）是负责内源性饱和脂肪酸棕榈酸酯合成的酶。与大多数正常细胞不同。恶性细胞依赖FASN活性来生长和存活。事实上，FASN在包括皮肤黑色素瘤在内的多种人类癌症中过表达，其表达水平与预后不良和侵袭深度相关。在这里。我们发现抗肥胖药物奥利司他或siRNA特异性抑制FASN活性能够显著降低小鼠转移性黑色素瘤细胞系B16-F10的增殖并促进细胞凋亡。这些结果促使我们在黑色素瘤自发性转移模型中验证FASN抑制对转移过程的影响，在C57BL/6小鼠腹腔注射B16-F10细胞转移到纵隔淋巴结。我们观察到，接种B16-F10细胞48小时后用奥利司他处理的小鼠，纵隔淋巴结转移的数量减少了52%。与对照动物相比。这些结果表明FASN活性对于B16-F10黑色素瘤细胞的增殖和存活至关重要，而奥利司他灭活FASN活性可显著减少其转移扩散。对FASN活性的化学抑制可能与当前黑色素瘤化疗相关。(C) 2008 Wiley-Liss, Inc。
Fatty acid synthase (FASN) is the enzyme responsible for the endogenous synthesis of the saturated fatty, acid palmitate. In contrast to most normal cells. malignant cells depend on FASN activity for growth and survival. In fact, FASN is overexpressed in a variety of human cancers including cutaneous melanoma, in which its levels of expression are associated with a poor prognosis and depth of invasion. Here. we show that the specific inhibition of' FASN activity by the antiobesity drug Orlistat or siRNA is able to significantly reduce proliferation and promote apoptosis in the mouse metastatic melanoma cell line B16-F10. These results prompted us to verify the effect of FASN inhibition on the metastatic process in a model of spontaneous melanoma metastasis, in which B16-F10 cells injected in the peritoneal cavity of C57BL/6 mice metastasize to the mediastinal lymph nodes. We observed that mice treated with Orlistat 48 hr after the inoculation of B16-F10 cells exhibited a 52% reduction in the number of mediastinal lymph node metastases. in comparison with the control animals. These results suggest that FASN activity is essential for B16-F10 melanoma cell proliferation and survival while its inactivation by Orlistat significantly reduces their metastatic spread. The chemical inhibition of F FASN activity could have a potential benefit in association with the current chemotherapy for melanoma. (C) 2008 Wiley-Liss, Inc.