Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer.
Apoptosis
/ drug effects
Carcinoma, Ovarian Epithelial
/ drug therapy
Cell Line, Tumor
Cisplatin
/ pharmacology
Collagen
/ metabolism
Drug Resistance, Neoplasm
/ drug effects
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Neoplasm Recurrence, Local
/ chemically induced
Ovarian Neoplasms
/ drug therapy
Oxidation-Reduction
/ drug effects
Signal Transduction
/ drug effects
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
20 04 2020
20 04 2020
Historique:
received:
21
11
2019
accepted:
19
03
2020
revised:
18
03
2020
entrez:
22
4
2020
pubmed:
22
4
2020
medline:
30
3
2021
Statut:
epublish
Résumé
Collagen type XI alpha 1 (COL11A1) is a novel biomarker associated with cisplatin resistance in ovarian cancer. However, the mechanisms underlying how COL11A1 confers cisplatin resistance in ovarian cancer are poorly understood. We identified that fatty acid β-oxidation (FAO) is upregulated by COL11A1 in ovarian cancer cells and that COL11A1-driven cisplatin resistance can be abrogated by inhibition of FAO. Furthermore, our results demonstrate that COL11A1 also enhances the expression of proteins involved in fatty acid synthesis. Interestingly, COL11A1-induced upregulation of fatty acid synthesis and FAO is modulated by the same signaling molecules. We identified that binding of COL11A1 to its receptors, α1β1 integrin and discoidin domain receptor 2 (DDR2), activates Src-Akt-AMPK signaling to increase the expression of both fatty acid synthesis and oxidation enzymes, although DDR2 seems to be the predominant receptor. Inhibition of fatty acid synthesis downregulates FAO despite the presence of COL11A1, suggesting that fatty acid synthesis might be a driver of FAO in ovarian cancer cells. Taken together, our results suggest that COL11A1 upregulates fatty acid metabolism in ovarian cancer cells in a DDR2-Src-Akt-AMPK dependent manner. Therefore, we propose that blocking FAO might serve as a promising therapeutic target to treat ovarian cancer, particularly cisplatin-resistant recurrent ovarian cancers which typically express high levels of COL11A1.
Identifiants
pubmed: 32312965
doi: 10.1038/s41419-020-2442-z
pii: 10.1038/s41419-020-2442-z
pmc: PMC7171147
doi:
Substances chimiques
Collagen
9007-34-5
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
258Subventions
Organisme : NCI NIH HHS
ID : R01 CA208753
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM088213
Pays : United States
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