NKX2-8 deletion-induced reprogramming of fatty acid metabolism confers chemoresistance in epithelial ovarian cancer.
Animals
Biomarkers
Carcinoma, Ovarian Epithelial
/ genetics
Cell Line, Tumor
Disease Models, Animal
Drug Resistance, Neoplasm
/ genetics
Fatty Acids
/ metabolism
Female
Gene Expression Regulation, Neoplastic
Homeodomain Proteins
/ genetics
Humans
Immunohistochemistry
In Situ Hybridization, Fluorescence
Mice
Models, Biological
Oxidation-Reduction
Prognosis
Protein Binding
Reactive Oxygen Species
/ metabolism
Sequence Deletion
Signal Transduction
Transcription Factors
/ genetics
Tumor Microenvironment
Chemoresistance
Epithelial ovarian cancer
Fatty acid oxidation
Metabolic reprogram
NKX2–8
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
May 2019
May 2019
Historique:
received:
25
12
2018
revised:
22
04
2019
accepted:
22
04
2019
pubmed:
3
5
2019
medline:
26
11
2019
entrez:
4
5
2019
Statut:
ppublish
Résumé
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). 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. 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 CPT1A 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. 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. FUND: This work was supported by Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities.
Sections du résumé
BACKGROUND
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
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
RESULTS
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 CPT1A 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
CONCLUSIONS
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. FUND: This work was supported by Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities.
Identifiants
pubmed: 31047858
pii: S2352-3964(19)30280-4
doi: 10.1016/j.ebiom.2019.04.041
pmc: PMC6562195
pii:
doi:
Substances chimiques
Biomarkers
0
Fatty Acids
0
Homeodomain Proteins
0
NKX2-8 protein, human
0
Reactive Oxygen Species
0
Transcription Factors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
238-252Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
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