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首页> 外文期刊>EBioMedicine >FASN Inhibition and Taxane Treatment Combine to Enhance Anti-tumor Efficacy in Diverse Xenograft Tumor Models through Disruption of Tubulin Palmitoylation and Microtubule Organization and FASN Inhibition-Mediated Effects on Oncogenic Signaling and Gene Ex
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FASN Inhibition and Taxane Treatment Combine to Enhance Anti-tumor Efficacy in Diverse Xenograft Tumor Models through Disruption of Tubulin Palmitoylation and Microtubule Organization and FASN Inhibition-Mediated Effects on Oncogenic Signaling and Gene Ex

机译：FASN抑制和紫杉烷处理相结合，通过破坏微管蛋白棕榈酰化和微管组织以及FASN抑制介导的致癌信号和基因表达，增强不同异种移植肿瘤模型的抗肿瘤功效。

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Palmitate, the enzymatic product of FASN, and palmitate-derived lipids support cell metabolism, membrane architecture, protein localization, and intracellular signaling. Tubulins are among many proteins that are modified post-translationally by acylation with palmitate. We show that FASN inhibition with TVB-3166 or TVB-3664 significantly reduces tubulin palmitoylation and mRNA expression. Disrupted microtubule organization in tumor cells is an additional consequence of FASN inhibition. FASN inhibition combined with taxane treatment enhances inhibition of in vitro tumor cell growth compared to treatment with either agent alone. In lung, ovarian, prostate, and pancreatic tumor xenograft studies, FASN inhibition and paclitaxel or docetaxel combine to inhibit xenograft tumor growth with significantly enhanced anti-tumor activity. Tumor regression was observed in 3 of 6 tumor xenograft models. FASN inhibition does not affect cellular taxane concentration in vitro. Our data suggest a mechanism of enhanced anti-tumor activity of the FASN and taxane drug combination that includes inhibition of tubulin palmitoylation and disruption of microtubule organization in tumor cells, as well as a sensitization of tumor cells to FASN inhibition-mediated effects that include gene expression changes and inhibition of @b-catenin. Together, the results strongly support investigation of combined FASN inhibition and taxane treatment as a therapy for a variety of human cancers.
机译：FASN的酶促产物棕榈酸酯和棕榈酸酯衍生的脂质支持细胞代谢，膜结构，蛋白质定位和细胞内信号传导。微管蛋白是许多通过棕榈酸酯酰化后翻译后修饰的蛋白质。我们显示，用TVB-3166或TVB-3664抑制FASN可以显着降低微管蛋白棕榈酰化和mRNA表达。肿瘤细胞中微管组织的破坏是FASN抑制的另一个结果。与单独使用任何一种药物进行处理相比，FASN抑制与紫杉烷处理相结合可增强对体外肿瘤细胞生长的抑制作用。在肺，卵巢，前列腺和胰腺肿瘤异种移植研究中，FASN抑制与紫杉醇或多西他赛联合使用可显着增强抗肿瘤活性，从而抑制异种移植肿瘤的生长。在6种肿瘤异种移植模型中，有3种观察到肿瘤消退。 FASN抑制不影响细胞紫杉烷的体外浓度。我们的数据表明，FASN和紫杉烷类药物组合具有增强的抗肿瘤活性的机制，包括抑制微管蛋白棕榈酰化和破坏肿瘤细胞中的微管组织，以及使肿瘤细胞对FASN抑制介导的影响（包括基因）表达变化和@ b-连环蛋白的抑制。总之，这些结果有力地支持了联合应用FASN抑制和紫杉烷治疗作为多种人类癌症疗法的研究。

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