期刊
EBIOMEDICINE
卷 43, 期 -, 页码 238-252出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2019.04.041
关键词
NKX2-8; Chemoresistance; Fatty acid oxidation; Metabolic reprogram; Epithelial ovarian cancer
资金
- Natural Science Foundation of China [81830082, 91740119, 91529301, 81621004, 91740118, 81773106, 81530082]
- Guangzhou Science and Technology Plan Projects [201803010098]
- Natural Science Foundation of Guangdong Province [2018B030311009, 2016A030308002]
- Fundamental Research Funds for the Central Universities [17ykjc02]
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.
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