PTGER3 induces ovary tumorigenesis and confers resistance to cisplatin therapy through up-regulation Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axis.
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Biomarkers
Cell Cycle
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Transformation, Neoplastic
/ genetics
Cisplatin
/ pharmacology
Drug Resistance, Neoplasm
/ genetics
Female
Gene Knockdown Techniques
Gene Silencing
Humans
Immunohistochemistry
Models, Biological
Ovarian Neoplasms
/ drug therapy
Proto-Oncogene Protein c-ets-1
/ metabolism
Receptors, Prostaglandin E, EP3 Subtype
/ genetics
Signal Transduction
/ drug effects
CFTR
Chemically modified siRNA
Cisplatin resistance
ELK1
ETS1
Ovarian cancer
PTGER3
RNA interference
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Feb 2019
Feb 2019
Historique:
received:
28
08
2018
revised:
07
11
2018
accepted:
21
11
2018
pubmed:
19
1
2019
medline:
27
6
2019
entrez:
19
1
2019
Statut:
ppublish
Résumé
Inflammatory mediator prostaglandin E2-prostaglandin E2 receptor EP3 (PTGER3) signaling is critical for tumor-associated angiogenesis, tumor growth, and chemoresistance. However, the mechanism underlying these effects in ovarian cancer is not known. An association between higher tumoral expression of PTGER3 and shorter patient survival in the ovarian cancer dataset of The Cancer Genome Atlas prompted investigation of the antitumor effects of PTGER3 downmodulation. PTGER3 mRNA and protein levels were higher in cisplatin-resistant ovarian cancer cells than in their cisplatin-sensitive counterparts. Silencing of PTGER3 via siRNA in cancer cells was associated with decreased cell growth and less invasiveness, as well as cell-cycle arrest and increased apoptosis, mediated through the Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axis. Furthermore, sustained PTGER3 silencing with multistage vector and liposomal 2'-F-phosphorodithioate-siRNA-mediated silencing of PTGER3 combined with cisplatin resulted in robust antitumor effects in cisplatin-resistant ovarian cancer models. These findings identify PTGER3 as a potential therapeutic target in chemoresistant ovarian cancers expressing high levels of this oncogenic protein. FUND: National Institutes of Health/National Cancer Institute, USA.
Sections du résumé
BACKGROUND
BACKGROUND
Inflammatory mediator prostaglandin E2-prostaglandin E2 receptor EP3 (PTGER3) signaling is critical for tumor-associated angiogenesis, tumor growth, and chemoresistance. However, the mechanism underlying these effects in ovarian cancer is not known.
METHODS
METHODS
An association between higher tumoral expression of PTGER3 and shorter patient survival in the ovarian cancer dataset of The Cancer Genome Atlas prompted investigation of the antitumor effects of PTGER3 downmodulation. PTGER3 mRNA and protein levels were higher in cisplatin-resistant ovarian cancer cells than in their cisplatin-sensitive counterparts.
FINDINGS
RESULTS
Silencing of PTGER3 via siRNA in cancer cells was associated with decreased cell growth and less invasiveness, as well as cell-cycle arrest and increased apoptosis, mediated through the Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axis. Furthermore, sustained PTGER3 silencing with multistage vector and liposomal 2'-F-phosphorodithioate-siRNA-mediated silencing of PTGER3 combined with cisplatin resulted in robust antitumor effects in cisplatin-resistant ovarian cancer models.
INTERPRETATION
CONCLUSIONS
These findings identify PTGER3 as a potential therapeutic target in chemoresistant ovarian cancers expressing high levels of this oncogenic protein. FUND: National Institutes of Health/National Cancer Institute, USA.
Identifiants
pubmed: 30655206
pii: S2352-3964(18)30549-8
doi: 10.1016/j.ebiom.2018.11.045
pmc: PMC6411965
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers
0
ETS1 protein, human
0
PTGER3 protein, human
0
Proto-Oncogene Protein c-ets-1
0
Receptors, Prostaglandin E, EP3 Subtype
0
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
290-304Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA160687
Pays : United States
Organisme : NCATS NIH HHS
ID : UH3 TR000943
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA098258
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA151668
Pays : United States
Organisme : NIGMS NIH HHS
ID : R44 GM086937
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA180145
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA096300
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA083639
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA093459
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2018. Published by Elsevier B.V.
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