Enhanced De Novo Lipid Synthesis Mediated by FASN Induces Chemoresistance in Colorectal Cancer.
Enhanced De Novo Lipid Synthesis Mediated by FASN Induces Chemoresistance in Colorectal Cancer.
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FASN 介导的增强脂质从头合成可诱导结直肠癌的化疗耐药性。
作者：
对奥沙利铂的耐药性威胁着结直肠癌（CRC）的预后。由于之前的研究引起了人们对癌症中脂肪酸代谢的兴趣，我们确定了脂肪酸生物合成是否会导致结直肠癌中的奥沙利铂耐药。通过利用 GEO 数据库，FASN 基因特征与基于奥沙利铂的化疗的反应和不良预后相关。此外，FASN 表达与体外奥沙利铂耐药性呈正相关。然后，奥利司他（一种典型的 FASN 抑制剂）被应用于减弱细胞培养和异种移植模型中对奥沙利铂的耐药性。此外，FASN 抑制剂和奥沙利铂的组合显着增加了细胞周期停滞并促进了细胞凋亡，部分原因是 MAPK/ERK 和 PI3K/AKT 途径的磷酸化减弱。我们的研究表明，FASN 增强了 CRC 对奥沙利铂的耐药性。抑制 FASN 可以通过调节 MAPK/ERK 和 PI3K/AKT 通路来挽救对奥沙利铂的反应。背景：奥沙利铂是结直肠癌（CRC）最广泛使用的化疗药物之一。对奥沙利铂的耐药性威胁着结直肠癌的预后。由于之前的研究引起了人们对癌症中脂肪酸代谢的兴趣，在这项研究中，我们确定了脂肪酸生物合成和相关的调节机制是否有助于结直肠癌中的奥沙利铂耐药。方法：在基因表达综合（GEO）数据库、奥沙利铂耐药细胞系和异种移植物中表征脂肪酸合酶（FASN）及其抑制剂奥利司他的作用。 mRNA-seq和分析确定了应用奥利司他后相关通路的变化，并通过Western blotting进行了验证。结果：通过利用 GEO 数据库，FASN 和密切相关的基因特征被确定与基于奥沙利铂的化疗的反应和不良预后相关。此外，FASN 表达上调促进了 CRC 细胞系对奥沙利铂的耐药性。然后，我们将奥利司他（一种典型的 FASN 抑制剂）应用于奥沙利铂耐药 CRC 的细胞培养和异种移植模型中，从而减弱了对奥沙利铂的耐药性。此外，FASN 抑制剂和奥沙利铂的组合显着增加了细胞周期停滞并促进了细胞凋亡，部分原因是 MAPK/ERK 和 PI3K/AKT 途径的磷酸化减弱。体内研究表明，用奥利司他抑制脂肪酸生物合成可以抑制异种移植肿瘤的生长，并增加对奥沙利铂的反应性。结论：我们的研究表明 FASN 增强了 CRC 对奥沙利铂的耐药性。 FASN 的抑制可以通过调节 MAPK/ERK 和 PI3K/AKT 通路来挽救对奥沙利铂的反应。
Resistance to oxaliplatin threatens the prognosis in of colorectal cancer (CRC). As previous studies have aroused interest in fatty acid metabolism in cancer, we determined whether fatty acid biosynthesis contribute to oxaliplatin resistance in CRC. By leveraging the GEO databases, FASN gene signatures was correlated with the response to oxaliplatin-based chemotherapy and poor prognosis. Additionally, FASN expression was positively related with oxaliplatin resistance in vitro. Then, Orlistat, a typical FASN inhibitor, was applied to attenuate the resistance to oxaliplatin in cell culture and xenograft models. Additionally, the combination of the FASN inhibitor and oxaliplatin significantly increased cell cycle arrest and facilitated apoptosis, partly due to the diminished phosphorylation of the MAPK/ERK and PI3K/AKT pathways. Our study revealed that FASN enhanced resistance to oxaliplatin in CRC. Inhibition of FASN could rescue the response to oxaliplatin by regulating MAPK/ERK and PI3K/AKT pathways. Background: Oxaliplatin is one of the most widely used chemotherapy drugs for colorectal cancer (CRC). Resistance to oxaliplatin threatens the prognosis of CRC. Since previous studies have aroused interest in fatty acid metabolism in cancer, in this study, we determined whether fatty acid biosynthesis and the related regulating mechanism contribute to oxaliplatin resistance in CRC. Methods: The effect of the fatty acid synthase (FASN) and its inhibitor Orlistat was characterized in Gene Expression Omnibus (GEO) databases, oxaliplatin-resistant cell lines, and xenografts. MRNA-seq and analysis identified related pathway changes after the application of Orlistat, which was verified by Western blotting. Results: By leveraging the GEO databases, FASN and closely related gene signatures were identified as being correlated with the response to oxaliplatin-based chemotherapy and poor prognosis. Additionally, FASN-upregulated expression promoted oxaliplatin resistance in CRC cell lines. We then applied Orlistat, a typical FASN inhibitor, in cell culture and xenograft models of oxaliplatin-resistant CRC, which attenuated the resistance to oxaliplatin. Additionally, the combination of the FASN inhibitor and oxaliplatin significantly increased cell cycle arrest and facilitated apoptosis, partly due to the diminished phosphorylation of the MAPK/ERK and PI3K/AKT pathways. In vivo studies showed that inhibiting fatty acid biosynthesis with Orlistat restrained the growth of xenograft tumors and increased the responsiveness to oxaliplatin. Conclusions: Our study revealed that FASN enhanced resistance to oxaliplatin in CRC. The inhibition of FASN could rescue the response to oxaliplatin by regulating MAPK/ERK and PI3K/AKT pathways.
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影响因子：
3.8
作者：
Belkaid A;Duguay SR;Ouellette RJ;Surette ME
通讯作者：
Surette ME
影响因子：
11.2
作者：
Rysman, Evelien;Brusselmans, Koen;Swinnen, Johannes V.
通讯作者：
Swinnen, Johannes V.
影响因子：
64.5
作者：
Chio IIC;Jafarnejad SM;Ponz-Sarvise M;Park Y;Rivera K;Palm W;Wilson J;Sangar V;Hao Y;Öhlund D;Wright K;Filippini D;Lee EJ;Da Silva B;Schoepfer C;Wilkinson JE;Buscaglia JM;DeNicola GM;Tiriac H;Hammell M;Crawford HC;Schmidt EE;Thompson CB;Pappin DJ;Sonenberg N;Tuveson DA
通讯作者：
Tuveson DA
影响因子：
2.4
作者：
Guo, Yu;Xiong, Bing-Hong;Ma, Li
通讯作者：
Ma, Li
影响因子：
9.7
作者：
Wang, Yun;Lu, Jia-Huan;Ju, Huai-Qiang
通讯作者：
Ju, Huai-Qiang