NKX2-8 deletion-induced reprogramming of fatty acid metabolism confers chemoresistance in epithelial ovarian cancer
NKX2-8 deletion-induced reprogramming of fatty acid metabolism confers chemoresistance in epithelial ovarian cancer
复制标题
NKX2-8缺失诱导的脂肪酸代谢重编程赋予上皮性卵巢癌化疗耐药性
DOI：
10.1016/j.ebiom.2019.04.041
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发表时间：
2019-05-01
期刊：
影响因子：
11.1
通讯作者：
Li, Jun
中科院分区：
文献类型：
--
作者：
Zhu, Jinrong;Wu, Geyan;Li, Jun
背景：脂肪酸（FA）代谢异常是肿瘤细胞特有的脆弱性，可能成为肿瘤治疗的新靶点。本研究旨在探讨NKX 2 -8缺失重编程FA代谢诱导上皮性卵巢癌（EOC）化疗耐药的分子机制。方法：采用荧光原位杂交和免疫组化方法检测144例EOC组织中NKX 2 -8的缺失频率和表达。NKX 2 -8缺失和脂肪酸氧化（FAO）拮抗剂Perhexiline对化疗耐药性的影响通过Annexin V和体外集落形成进行了研究，并通过腹腔内肿瘤模型进行了体内研究。使用Chip-seq、代谢组学分析、FAO测定和免疫沉淀测定确定了NKX 2 -8缺失在重编程FA代谢中的机制。结果：NKX 2 -8缺失与EOC患者的总体和无复发生存率相关。NKX 2 -8通过表观遗传学抑制FAO级联的多个关键组分（包括CPTIA和CPT 2）来抑制FAO途径。NKX 2 -8的缺失导致脂肪微环境中EOC细胞FA代谢的重编程，并导致铂耐药。重要的是，FAO途径使用哌己西林的药理学抑制显着抵消NKX 2 -8删除诱导的化疗耐药性和增强铂的治疗效果在EOC.Interpretation：我们的研究结果表明，NKX 2 -8删除重编程FA代谢有助于化疗耐药性和哌己西林可能作为一个潜在的定制治疗NKX 2 -8删除EOC患者。(C)2019年，任作家。由爱思唯尔公司出版
Background: Aberrant fatty acid (FA) metabolism is a unique vulnerability of cancer cells and may present a promising target for cancer therapy. Our study aims to elucidate the molecular mechanisms by which NKX2-8 deletion reprogrammed FA metabolism-induced chemoresistance in epithelial ovarian cancer (EOC).Methods: The deletion frequency and expression of NKX2-8 in 144 EOC specimens were assayed using fluorescence in situ hybridization and immunochemical assays. The effects of NKX2-8 deletion and the fatty acid oxidation (FAO) antagonist Perhexiline on chemoresistance were examined by Annexin V and colony formation in vitro, and via an intraperitoneal tumor model in vivo. The mechanisms of NKX2-8 deletion in reprogrammed FA metabolism was determined using Chip-seq, metabolomic analysis, FAO assays and immunoprecipitation assays.Findings: NKX2-8 deletion was correlated with the overall and relapse-free survival of EOC patients. NKX2-8 inhibited the FAO pathway by epigenetically suppressing multiple key components of the FAO cascade, including CPTIA and CPT2. Loss of NKX2-8 resulted in reprogramming of FA metabolism of EOC cells in an adipose microenvironment and leading to platinum resistance. Importantly, pharmacological inhibition of FAO pathway using Perhexiline significantly counteracted NKX2-8 deletion-induced chemoresistance and enhanced platinum's therapeutic efficacy in EOC.Interpretation: Our results demonstrate that NKX2-8 deletion-reprogrammed FA metabolism contributes to chemoresistance and Perhexiline might serve as a potential tailored treatment for patients with NKX2-8-deleted EOC. (C) 2019 The Authors. Published by Elsevier B.V.