PTGER3 induces ovary tumorigenesis and confers resistance to cisplatin therapy through up-regulation Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axis

Cristian Rodriguez-Aguayo, Emine Bayraktar, Cristina Ivan, Burcu Aslan, Junhua Mai, Guangan He, Lingegowda S. Mangala, Dahai Jiang, Archana S. Nagaraja, Bulent Ozpolat, Arturo Chavez-Reyes, Mauro Ferrari, Rahul Mitra, Zahid H. Siddik, Haifa Shen, Xianbin Yang, Anil K. Sood, Gabriel Lopez-Berestein

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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: 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: 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: 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.

Original languageEnglish (US)
Pages (from-to)290-304
Number of pages15
JournalEBioMedicine
Volume40
DOIs
StatePublished - Feb 2019

Keywords

  • CFTR
  • Chemically modified siRNA
  • Cisplatin resistance
  • ELK1
  • ETS1
  • Ovarian cancer
  • PTGER3
  • RNA interference

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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